JP2023534635A - Nasal hygiene compositions, antimicrobial treatments, devices and articles for delivery to the nose, trachea and main bronchi - Google Patents

Abstract

Salt-based non-therapeutic hygiene formulations or compositions or therapeutic formulations or compositions (e.g., calcium-rich) are effective against airborne pathogens and toxins, e.g., airway lining fluid. Suppresses shedding by increasing surface viscoelasticity. Related devices, methods and articles are used to deliver salt-based non-therapeutic hygienic formulations or compositions to the upper respiratory tract as a hygienic treatment. Related devices, methods and articles are used to deliver salt-based therapeutic antimicrobial formulations or compositions to the upper respiratory tract. For example, nasal delivery of calcium-rich saline with an aerosol droplet size of about 10 μm (eg, 7 μm to 15 μm, or more preferably 9 μm to 10 μm) advantageously limits distribution to the nose and upper respiratory tract. and can suppress bioaerosol generation. A nebulizer may deliver an aerosol into free space or into a partially enclosed volume, where the composition is naturally inhaled by one or more subjects.

Description

The present disclosure generally relates to nasally administered salt-based formulations or compositions, e.g., mass median diameter (or mass median diameter/mass median diameter) and therapeutic protocols, devices suitable for delivery of the salt-based composition as an aerosol to the nasal, tracheal and/or main bronchi of the respiratory tract of a subject. and suppression of exhaled aerosol particles from the upper airways of the human respiratory tract (ie, nose, pharynx, larynx, trachea and/or main bronchi) via articles.

Description of the Related Art Various diseases are caused by viruses, bacteria, and other inhaled foreign substances. At least some viruses, such as variations (or variants) of influenza viruses and variations of coronaviruses, are transmitted, at least in part, via respiratory transmission. An example of an airborne bacterial infection is tuberculosis. In one mechanism, a person infected with a microbe releases the microbe through disruption of airway lining fluid (or upper airway lining fluid) by breathing, coughing, sneezing, talking, or even singing. It can erupt and expose others to microbes through airborne transmission. The ejected microorganisms may also be drawn deeper into the subject's airways, eg, into the lungs. Inhaled particles from the environment, such as soot particles, can land mucus in the upper airway lining mucus. Dispersal of mucus into respiratory droplets can carry these particles deep into the lungs, promoting allergic reactions and other respiratory ailments.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is caused by large droplets exhaled when a person coughs or sneezes and very small droplets that form in the airways when a person breathes naturally. propagates through the air by How breath droplets vary between individuals, evolve over time within an individual, and change with the onset and progression of COVID-19 infection can contribute to the spread of COVID-19 and other contagious diseases such as influenza and tuberculosis. It is important for clarifying the nature of highly airborne respiratory diseases.

The delivery of therapeutic agents to the nasal epithelium and other parts of the upper respiratory tract to modulate human health, such as in the delivery of active agents to relieve symptoms associated with congestion or asthma, generally involves sprays, Including active (forced) delivery of dry or liquid formulations to the nose via metered dose inhalers, or dry powder inhalers. The use of these substances to combat infections is generally limited to antibiotics or antivirals. Delivery of pure nasal hygiene substances, such as in sodium chloride, to cleanse mucus is also common. Applicants are not aware of any nasal hygiene specifically targeted against infections in such a way that washing hands or wearing a mask would provide protection against infections.

The ability to return to normal activity in the face of an airborne disease pandemic of the kind that COVID-19 poses will be critical to airborne hygiene in the vicinity of the nose, trachea and main bronchi, where infections often begin and significant bioaerosol emissions occur. may depend on the ability to provide targeted protection. Such would be important from a personal point of view as well, for example, for crowds where social distancing cannot be ensured. This same hygiene protection would be beneficial against other airborne diseases such as influenza, and would also be useful in promoting respiratory health in individuals exposed to high levels of air pollution.

Given the widespread disease potential from inhalation of foreign particles, as evidenced by the ongoing COVID-19 pandemic, a reduction in respiratory droplet production in the upper respiratory tract and thus suppression of exhaled droplets or bioaerosols New approaches to effectively deliver hygienic and therapeutic substances to prevent disease are desirable.

The generation of respiratory droplets during exhalation can be caused by the force of rapid air currents that occur in the upper respiratory tract during breathing, talking, coughing, and sneezing. At peak inspiratory flow during normal breathing, air velocities in the trachea and main bronchi can reach turbulent velocities. A sudden outflow of air over the thin (5 μm-10 μm) mucus layer lining the upper respiratory tract can break the mucus surface into small droplets, much like a strong wind breaks down and sprays onto the surface of the ocean. The nature and extent of this droplet breakup depends on the surface properties of the mucus itself. Among the properties that affect droplet formation and droplet size are surface viscoelasticity (which resists stretching of the mucus surface upon breakage) and surface tension (which reduces the energy expended to form small droplets). be. In airway mucus, both properties vary with the type and concentration of lung surfactant, surface particle concentration, and composition and structure of the mucus adjacent to the air surface. Thus, for example, surfactants driven in part by accumulation of particles by breathing polluted air or growth of pathogens, or by physiological changes in the human condition, including diet, aging, and COVID19 infection itself. and mucin composition and structural changes can be expected to alter droplet formation and droplet size during the action of respiration.

The scientific response to the COVID-19 pandemic has largely focused on developing therapeutic drugs and preventive vaccines. While waiting for a cure or herd immunity, the scientific community may be encouraged to focus more on managing COVID-19, in part through a reduction in respiratory droplet production reflected in exhaled particle counts. In particular, typical masks do not stop all the most numerous sub-micron particles in the air exhaled by infected individuals. For example, approximately 85% of respiratory particles (inhaled and exhaled) are believed to be in the submicron size range. In addition to more effective masks and more sophisticated social distancing rules, approaches that stabilize mucus-lined airways and preserve mucus clearance function would be particularly useful.

In particular, exhaled aerosol counts are considered not only an indicator of disease progression, but also a marker of disease risk in uninfected individuals. Diagnostic monitoring is also considered an important strategy to consider in controlling the transmission and infection of COVID-19 and other respiratory infections, including influenza.

Nasal administration of physiological salts is believed to be particularly effective in reducing airborne particles from exhaled breath, including submicron aerosolized particles that are not effectively filtered by cloth face masks. For example, nasal application of drug-free calcium-enriched nasal salts interacts with airway mucosal mucus to cleanse the airways of bioaerosols that can reduce exhaled aerosol particles by up to 99% and exhaled particles in a large cohort of human subjects. The overall reduction in is about 75%. Irrigation not only reduces exhalation of particles, but can also reduce further inhalation of particles into the respiratory tract (eg, lower respiratory tract). Nasal administration of physiological salts could be an important addition to current COVID-19 hygiene protocols of mask wearing, hand washing, and social distancing. Nasal administration of physiological salts adds to the efficacy of the mask in reducing penetration of respiratory droplets into the lungs or backflow into the environment, and provides an additional layer of protection when mask-wearing is not possible.

The global crisis caused by the rapid and persistent spread of COVID-19 points to inadequate protection against current airborne diseases. Nasal administration of physiological salts, particularly calcium-enriched physiological salts, can be used to address the challenges that the airborne route of infection and transmission presents to public health. There is a particular need for purely hygienic compositions and methods for cleansing the airways of droplets of airway-lining fluid, such as those that occur during spontaneous breathing, talking, coughing and sneezing. In a study of 10 human volunteers (5 younger than 65 years, 5 older than 65 years), a mean diameter of 9-10 μm was rapidly (eg within 15 minutes) and durable (eg within at least 6 hours) 5-15 seconds of delivery of nasal saline containing calcium and sodium salts with , perceivable lower airways (i.e., secondary bronchi, tertiary bronchi, bronchi, terminal bronchi of the lung) beyond the trachea and primary or main bronchi reduces respiratory particles from the human airway without penetrating into the airways. Primarily below 1 μm, these exhaled particles are below the size that is effectively filtered by conventional masks. In contrast, in the same study, delivery of a similar calcium-enriched nasal saline solution with mean diameter droplets of 2-4 μm required several minutes for administration and a more uniform distribution of exhaled particles from the human airways. It produces inhibition while also penetrating the lungs beyond the trachea and main bronchi. Delivery of isotonic saline (sodium chloride) by small aerosols (2-4 μm droplets) to the lung has a milder effect on suppression, as shown in the same study in 2004. . In the same study of 10 volunteers, delivering isotonic saline to the nose by large droplets ranging from about 10-300 μm with an average diameter of about 40-50 μm had no effect on exhaled aerosol. . However, in a recent study, delivery of this same aerosol with a similarly large droplet diameter showed that head tilting to allow retronasal instillation significantly suppressed exhaled aerosol. These results are consistent with known deposition patterns of inhaled aerosols. In particular, droplets in the 1-5 μm range tend to penetrate and deposit throughout the airways, including the alveolar regions of the lungs. Generation of a given mass for deep lung delivery with small droplets in this size range requires more energy than generation of the same mass for delivery in droplets of size e.g. , requires more time for a given energy input. Inhaled droplets with a diameter of around 10 μm are mainly deposited in the nasopharynx, trachea and main bronchi. On the other hand, 15-300 μm droplets can be sprayed intranasally, but tend to land in the nose and do not penetrate the trachea. A solution deposited in the nose can drip into the trachea and main bronchi via postnasal drip. Although other divalent cations can be delivered to the respiratory tract for the purpose of inhibiting respiratory droplet formation, calcium is particularly desirable in that it is present in the body in relatively high concentrations. Magnesium is also present in the body, but at low concentrations (approximately 5-10 times lower than calcium concentrations) and acts slower than calcium on negatively charged molecules such as mucin and alginate. Other divalent and polyvalent cations can be effective, but are either foreign to the body, as in the case of chitosan, or are present in the body, as in the case of iron, whereas other Introduce complex biochemical consequences.

Exhaled droplet suppression by nasal delivery of sodium chloride and other additives including lavender, cinnamon, lemongrass, and alcohol - with and without - calcium-rich saline is from about 7 μm to about 15 μm, and preferably is associated with an aerosol droplet median diameter of about 10 μm (eg, 9 μm-10 μm), suggesting the upper respiratory tract (ie, nose, pharynx, larynx, trachea, and main bronchi) as the major source of bioaerosol generation. The suppressive effect is particularly pronounced among people who exhale large numbers of particles (99%). High particle exhalation appears to correlate with advanced age and body mass index (BMI), as does pulmonary infection and long-term exposure to high airborne particulate aerosol loads.

New hygienic practices of "airway hygiene" proposed using calcium-rich saline nasal solution to complement widely recommended hand washing with common soaps, use of face masks, and social distancing be done. Airway hygiene may soon be introduced next to these other hygiene measures.

Combinations of hygiene and treatment are also desirable, whether with combinations of salts shown to produce antimicrobial effects, or with other therapeutically active substances.

Individuals known or suspected of having an airborne illness (e.g., infection with COVID-19 and other respiratory infections, including influenza) or known or suspected of having an airborne illness There is also a need for therapeutic compositions and methods for treating the respiratory tract of individuals who have been exposed to other individuals.

A new therapeutic practice is the nasal application of calcium-rich saline aerosols, with or without other therapeutically active substances, to the upper respiratory tract, with or without other salts that have been shown to produce antimicrobial effects. be written. Nasal application of physiological salts, particularly droplet aerosols containing calcium-rich salts (e.g., calcium chloride) of size-restricted aerosols primarily to the upper respiratory tract, is beneficially antibacterial and/or or may produce an anti-pathogen effect.

In particular, a targeted mister or nebulizer that delivers an aerosol with a high concentration of calcium to the upper airway site of respiratory droplet formation may be particularly effective. Calcium-rich salt ions can associate with the mucins on the surface of the airways that line the mucus and enhance the mucus' resistance to breakdown. This can advantageously cleanse the airways of respiratory droplets that can carry infections and insoluble environmental contaminants.

Otherwise, a calcium-rich salt solution applied to the nose by spray, combined with a tilted-back or reclining position of the head that promotes nasal post-instillation, can result in high concentrations of calcium or other polycationic compounds. Another method for delivering molecules to the upper airway site of respiratory droplet formation.

Hygienic and therapeutically active substances are deposited in the nose with some efficiency, depending on the nature of the delivery system and technology. This efficiency can be measured as a ratio of the "delivered dose" to the "nominal dose" and delivery of substances to the nasal epithelium occurs in two ways. First, nasal fragrance delivery occurs by inhaling atmospheric substances directly through, for example, the nostrils or nasal vestibule. Second, post-nasal scent delivery is achieved by the natural diffusion and convection of oral substances into the nasal cavity via the oropharynx. This latter delivery is called reverse nasal olfaction and is facilitated by exhalation.

Novel salt-based sanitary and/or antimicrobial formulations or compositions effective against airborne pathogens and other airborne contaminants, and delivery of salt-based antimicrobial and/or anti-infective formulations or compositions. Related apparatus, methods and articles for are described herein. The salt-based sanitary and/or antimicrobial formulations or compositions, devices, methods and articles described reduce the shedding of aerosol particles of airway lining fluids (bioaerosols) either on an individual basis or in groups of individuals or groups. can be advantageously used to suppress or otherwise reduce the The approach described uses a combination of ortho-nasal and retro-nasal delivery, the former occurring on inspiration of physiological salt solutions and the latter on exhalation of these same salt solutions. happens at times. The salt-based formulation or composition has a mass median droplet diameter (mass median droplet diameter) range of about 7 microns to about 15 microns in a readily soluble solution applied to the nose as a device or spray. Alternatively, a mass median droplet diameter of about 9 to about 10 microns, about 9.5 microns, or about 10 microns , with a standard deviation of less than 1 micron. These droplet diameter ranges are advantageously too large for significant penetration into the lungs, while small enough to be transported through the nose to the trachea and main bronchi of the respiratory tract.

Salt-based sanitary and/or antimicrobial formulations or compositions may preferably be enriched with calcium or magnesium (eg calcium chloride or magnesium chloride). Suitable salt-based sanitary and/or antibacterial formulations or compositions rich in calcium or magnesium are, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8% _CaCl2 or a salt solution containing MgCl ₂ ; or 4.0-6.0% CaCl ₂ or MgCl ₂ . These CaCl ₂ or MgCl ₂ solutions may further contain NaCl, such as 0.1%, 0.5%, 1.0%, or 1.5% NaCl; 5%, 0.5-1.5%, or 0.1-0.5% NaCl. In another embodiment, the salt-based composition does not contain any NaCl in the composition. In another embodiment, the salt-based composition has no more than 0.1 wt% NaCl in the composition. Percentages can be wt % based on the total amount of the salt-based composition in the droplets or other amount of solution containing the salt (eg, water, other solvent). As the examples show, the salt-based component can include 4.72% _CaCl2 and 0.31% NaCl, or 1.29% _CaCl2 and 0.9% NaCl.

Salt-based solutions may also optionally contain one or more preservatives. Preservatives can include any preservative that does not otherwise interfere with the chemical nature of the salts in salt-based formulations. As those skilled in the art will appreciate, preservatives are on the FDA list of non-active agents. Suitable preservatives include benzalkonium chloride, benzyl alcohol and benzoic acid. Preservatives can be added in amounts known to those skilled in the art, eg, 0.05-0.2% by weight, or about 0.1% by weight. Alternatively, or in addition, the salt-based solution may also be added via the addition of HCl, or some other means, such as from about 2 to about 6; alternatively from about 2 to about 5; from about 2 to about 3; It can have a low pH through a pH range of about 2.5. HCl acid can be added along with the citrate buffer.

Alternatively, formulations of CaCl ₂ with lavender, cinnamon, lemongrass, and ethanol are all effective, among other essential oils and flavor extracts. The essential oil, aromatic oil and flavor extract compositions can take any of a wide variety of forms and can be mixed with water (eg distilled or sterile water). For example, start with a 25 milliliter vial of water. 0.025-1 ml of essential oil, aromatic oil or flavor extract of cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil, palm oil, fig oil, grapefruit oil, hazelnut oil, hazelnut melon oil, Lavender or spike lavender oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise extract, and/or Or added as in linalool or linalool-containing essential oils. As an example, if the mass of the cloud dispersed in front of the nose is less than 100 milligrams total mass, the total amount of ginger can be less than about 100 micrograms.

Application may be simple, for example, one or more deep nasal inhalations may reduce exhaled aerosol by up to 75%, or even up to 99%, up to 6 hours after administration. A protocol for administration can include, for example, application upon arrival at a location (eg, work site) prior to masking. Initial applications (eg, two deep breaths) may be administered by staff or other individuals assigned to a particular task. A second application (eg, two deep breaths) may follow, for example, during a meal (eg, lunch) break. A second use can be, for example, self-administration. Self-administration may be performed from a freely accessible wall and/or table mounted nebulizer or mister and advantageously includes a hand sanitizer dispenser mounted or located in close proximity to the nebulizer or mister. obtain. Alternatively, each individual (e.g., employee) is supplied with a personal nebulizer or mister and an appropriate supply of calcium-rich solution or dry powder to enable the individual to self-administer calcium-rich airway hygiene. (eg, 3 times a day). Training can be advantageously provided, especially when self-administration is used.

Various devices are also described herein that enable ambulatory and discrete delivery of salt-based sanitary and/or antimicrobial formulations or compositions, and increase the efficiency of delivery to humans and other animals on an individual basis. Advantageously, the device is configured to be portable, allowing the user to control, for example, viral shedding and/or to unwanted airborne contaminants (e.g., smoke and other airborne toxins). It is possible to have the benefits of on-demand delivery in a wide variety of environments in order to limit the exposure of (eg, deep lung) to.

There are also various devices that enable mass delivery of salt-based formulations or compositions to groups (e.g., two or more individuals, crowds, processions of individuals) and increase the efficiency of delivery to humans and other animals on a group basis. described herein. Such may be fixed or portable devices. Such are suitable for use with stadiums, other venues, and/or crowds at various events.

In addition, individuals, e.g., those known or suspected of having an airborne disease (e.g., infection with COVID-19 and other respiratory communicable diseases, including influenza), or who have an airborne disease. There is a need for diagnostic methods and devices for monitoring respiratory droplet emissions from other individuals known or suspected to have or from individuals breathing contaminated air over an extended period of time. A diagnostic method includes sampling exhaled breath of a subject, determining a metric that characterizes the amount of exhaled breath droplets shed during exhalation, and determining the metric as a level of disease risk and/or contagious or contagious risk. correlating with categories indicative of at least one of levels or levels of recommended isolation precautions to be taken. Metrics may take the form of, for example, counts or approximate counts of exhaled droplets and/or pathogens present, or another representation of aerosol counts. Breath sampling may be performed over a defined number of breaths or over a defined period of time. Correlation can be performed on a representative sampling of breath samples taken from a representative sample of the population.

Accordingly, one implementation includes (a) aerosol droplets comprising a salt-based composition comprising from about 1% to about 10% by weight calcium chloride and/or magnesium chloride (eg, percentage per droplet) in water can be summarized as the composition of The droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns. In some implementations, the composition of the aerosol droplets comprises (b1) a preservative selected from the group consisting of benzalkonium chloride, benzoic acid, and benzoyl alcohol, or (b2) the pH of the salt-based composition. can include a sufficient amount of acid to reduce the to about 2 to about 6. In some embodiments, either (b1) a preservative or (b2) an acid may be present.

Another implementation can be summarized as a composition comprising (a) a dry powder containing calcium and/or magnesium chloride; and (b) a sterile solution. A sterile solution may consist of water (eg, sterile water). In some implementations, the water-based composition includes (1) a preservative selected from the group consisting of benzalkonium chloride, benzoic acid, and benzoyl alcohol, or (2) the pH of the salt-based composition. Sufficient amounts of acid to reduce from about 2 to about 6 can be included. Dry powders can be mixed with water or water-based compositions to form salt-based compositions.

Another implementation can be summarized as a method of administering a formulation or composition to the nose, trachea, and major bronchi of a subject's respiratory tract. The method involves generating an aerosol of droplets in the nose, trachea, and main bronchi of the subject's respiratory tract within a space that is naturally inhalable by the subject without the application of force. The droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water, and the droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns.

Another implementation can be summarized as a method of suppressing exhalation of particles in the upper airway of a subject's airway. The method involves generating an aerosol of droplets and administering the aerosol of droplets to airway lining fluid in the nose, trachea, and main bronchi of a subject, thereby exhaling particles in the subject's upper respiratory tract. including suppressing The droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water droplets, the droplets having a mass median droplet diameter ranging from about 7 microns to about 15 microns, The drops are suspended in a standing cloud.

Another implementation can be summarized as a delivery system operable to deliver a purely hygienic or antimicrobial formulation or composition to the nose, trachea and main bronchi of a subject's respiratory tract. The delivery system includes a reservoir having at least one wall that at least partially separates an interior of the reservoir from an exterior thereof, the reservoir having a port that provides a fluid communication path between the interior of the reservoir and the exterior thereof; The reservoir holds, at least at the time of use, a sanitary or antimicrobial formulation or composition comprising a quantity of water and at least calcium chloride and/or magnesium chloride dissolved in the water. The delivery system also includes at least one nebulizer delivery device, the at least one nebulizer delivery device including a reservoir and an actuator, the actuator having a mass median diameter range of about 7 microns to about 15 microns, and an amount of water is controllably operable on the active agent medium to cause the formation of an aerosol comprising readily soluble droplets comprising at least calcium chloride dissolved in .

Another embodiment can be summarized as a kit for suppressing exhalation of particles in the upper respiratory tract of a subject. The kit includes a measured amount of calcium chloride and/or magnesium chloride; a container sized to receive a defined amount of water for dissolving the calcium chloride therein; and instructions.

Another implementation can be summarized as a method of administering a formulation or composition to the nose, trachea, and major bronchi of a subject's respiratory tract. The method involves generating an aerosol of droplets in the nose, trachea, and main bronchi of the subject's respiratory tract within a space that is naturally inhalable by the subject without the application of force. Droplet aerosols include salt-based compositions comprising calcium chloride and/or magnesium chloride in water. A method of administering a formulation or composition to the nose, trachea, and main bronchi of a subject's respiratory tract is accomplished by spraying the salt-based composition into the subject's nose, while the subject is on the head. Lean back or in a reclined position to facilitate post-nasal drip.

Another embodiment comprises (a) from about 1% to about 5% by weight calcium chloride in water; and (b1) a benzalkonium chloride preservative, or (b2) the pH of the salt-based composition from about 2 to about It can be summarized as a composition of aerosol droplets containing a salt-based composition containing a sufficient amount of acid to reduce the amount to 3. Advantageously, although this method is not limited by droplet size, the ranges described can still be used effectively with this method, eg, in the 20-30 mg dose range.

Salt-based non-therapeutic hygiene formulations or compositions or therapeutic formulations or compositions (e.g., calcium-rich) are effective against airborne pathogens and toxins, e.g., airway lining fluid. Suppresses shedding by increasing surface viscoelasticity. Related devices, methods and articles are used to deliver salt-based non-therapeutic hygienic formulations or compositions to the upper respiratory tract as a hygienic treatment. Related devices, methods and articles are used to deliver salt-based therapeutic antimicrobial formulations or compositions to the upper respiratory tract. For example, intranasal delivery of calcium-rich saline having an aerosol droplet size of about 10 μm (eg, 7 μm to 15 μm, or more preferably 9 μm to 10 μm) advantageously provides distribution to the nose and upper airways of the respiratory tract. can limit the bioaerosol generation/efflux of pathogens and toxins. A nebulizer or pump with a micron-scale orifice () can deliver an aerosol into free space or into a partially enclosed volume, and the composition can be inhaled by one or more subjects (e.g., usually naturally inhaled by breathing).

In the drawings, identical reference numbers indicate similar elements or acts. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale, and some of these elements are arbitrarily enlarged and positioned to improve drawing legibility. Furthermore, the specific shapes of the elements shown are not necessarily intended to convey information as to the actual shape of the particular elements, but have been selected for clarity only.
FIG. 1A depicts a delivery device for delivering an aerosol of a salt-based sanitary and/or antimicrobial formulation or composition into an unconfined space or volume to be inhaled by a subject, according to at least one illustrated embodiment. Fig. 4 is an angular projection;
FIG. 1B illustrates either a non-confined or free space or volume using a delivery device for delivering an aerosol of a salt-based sanitary and/or antimicrobial formulation, according to at least one illustrated implementation. Various continuous doses performed using a delivery device to deliver to or to a confined space or volume (e.g., mask, tumbler, glass, vial beaker, or other container) that is inhaled by a subject. FIG. 4 is an exemplary diagram of operations;
FIG. 2A shows a salt-based hygienic and/or antimicrobial formulation or composition that exhibited relatively high viral shedding exhaled from two human volunteers prior to administration, according to at least one exemplified implementation. 4 is a bar graph showing particles;
FIG. 2B shows relatively average viral shedding exhaled from eight volunteers prior to administration of a salt-based hygienic and/or antimicrobial formulation or composition, according to at least one exemplified practice. Fig. 3 is a bar graph showing particles that have been collected;
FIG. 3 is a line graph showing exhaled particles from 10 human volunteers after administration of a salt-based hygienic and/or antimicrobial formulation or composition, according to at least one exemplary implementation; .
FIG. 4A shows particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified implementation. graph.
FIG. 4B shows particles exhaled per subject after administering a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 4C shows particles exhaled per subject after administering a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 4D is a graph showing particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified implementation; be.
FIG. 4E shows particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 4F shows particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 4G shows particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 4H is a graph showing particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice; is.
FIG. 4I shows particles exhaled per subject after administration of a salt-based hygienic and/or antimicrobial formulation or composition compared to a placebo control, according to at least one exemplified practice. graph.
FIG. 5 is a schematic diagram of a portion of a delivery device comprising a screen and at least one piezoelectric element, solenoid or electric motor physically coupled to move the screen; The device also includes one or more of a radio, a transducer or sensor, and a switch communicatively coupled to a control system, such as a microcontroller and memory, and at least one operatively coupled to control operation of the nebulizer, according to one illustrated embodiment;
FIG. 6A delivers a mist, cloud, or aerosol comprising a salt-based hygienic and/or antimicrobial formulation or composition effective against airborne pathogens, according to at least one illustrated embodiment; FIG. 6 is an exploded view of the delivery device of FIG. 5 for
FIG. 6B delivers a mist, cloud, or aerosol comprising a salt-based sanitary and/or antimicrobial formulation or composition effective against the airborne pathogens of FIG. 6A, according to at least one illustrated embodiment; 1 is a perspective view of a delivery device for.
FIG. 6C depicts a mist, cloud comprising salt-based sanitary and/or antimicrobial and/or formulations or compositions effective against airborne pathogens of FIGS. 6A and 6B, according to at least one illustrated embodiment. , or a side view of a delivery device for delivering an aerosol.
FIG. 6D depicts a mist, cloud, or aerosol comprising a salt-based sanitary and/or antimicrobial formulation or composition effective against the airborne pathogens of FIGS. 6A-6C, according to at least one illustrated embodiment. 1 is a cross-sectional side view of a delivery device for delivering; FIG.
FIG. 6E depicts a mist, cloud, or aerosol comprising a salt-based sanitary and/or antimicrobial formulation or composition effective against the airborne pathogens of FIGS. 6A-6D, according to at least one illustrated embodiment. FIG. 4 is a side view of components of a delivery device for delivery;
FIG. 6F depicts a mist, cloud, or aerosol comprising a salt-based sanitary and/or antimicrobial formulation or composition effective against the airborne pathogens of FIGS. 6A-6D, according to at least one illustrated embodiment. FIG. 10 is another side view of components of a delivery device for delivering;
FIG. 7A depicts a mist, cloud, or mist comprising a salt-based sanitary and/or antimicrobial formulation or composition effective against the airborne pathogens of FIGS. 6A-6F, according to at least one illustrated embodiment. FIG. 2 is a rear view of a printed circuit board and associated components connected thereto for use in a delivery device for delivering an aerosol;
7B is a side view of the printed circuit board and associated components of FIG. 7A, in accordance with at least one illustrated embodiment; FIG.
FIG. 7C is a front view of the printed circuit board and associated components of FIGS. 7A and 7B, according to at least one illustrated embodiment;
FIG. 7D is a perspective view of the printed circuit board and associated components of FIGS. 7A-7C, according to at least one illustrated embodiment.
FIG. 7E is a rear view of the printed circuit board of FIGS. 7A-7D without associated components coupled to the printed circuit board of FIGS. 7A-7D, according to at least one illustrated embodiment.
FIG. 7F is a side view of the printed circuit board of FIGS. 7A-7D without associated components coupled to the printed circuit board of FIGS. 7A-7D, according to at least one illustrated embodiment.
FIG. 7G is a front view of the printed circuit board of FIGS. 7A-7D without associated components coupled to FIGS. 7A-7D, according to at least one illustrated embodiment.
FIG. 7H is a front view of an alternative configuration of the printed circuit board of FIGS. 7A-7D without the relevant components of FIGS. 7A-7D bonded thereto, according to at least one illustrated embodiment.
Figure 8 shows the general design of the protocol for the three research sites, specifically the GRCC research site discussed in the experimental section.
Figures 9A, 9B and 9C are shown for 40 human volunteers at Bangalore (Figure A), 120 human volunteers at Grand Rapids (Figure 9B), and 93 human volunteers at Cape Cod (Figure 9C). Results are presented in terms of exhaled aerosol particle number and size.
Figures 10A and 10B show exhaled aerosol counts for 20 subjects 15 minutes after administration of composition A (Figure 10A) and several hours after administration of composition A.
Figures 10C and 10D show the inhibitory effect after administration of Composition A for total exhaled aerosol in all 40 subjects at 2 hours post-dose versus nasal saline controls.
11A, 11B, and 11C show exhaled aerosols from all subjects before and 15-30 minutes after administration of Composition A or plain saline versus Composition A. compare the effectiveness of Results for the 20% highest emission aerosol subject are shown in Figures 11A-C (Composition A).
Figures 12A, 12B and 12C show the extent of overall suppression of exhaled aerosol at each site 15-20 minutes after administration for both Composition A and plain saline. Although overall airway cleaning with the Simply Saline control was not significant in all cases (BBH p<0.94, GRCC p<0.83, CCA p<0.65), the overall Composition A airway cleaning effect was Slightly significant for each site tested (BBH p<0.169, GRCC p<0.124, CCA p<0.098).
FIG. 13A is a bar graph showing exhaled particle counts from a study of a set of human subjects who exhibited mild COVID-19 symptoms prior to treatment, according to at least one illustrated implementation.
FIG. 13B is a bar graph showing baseline values for human subjects as a function of duration of infection, according to at least one illustrated implementation.
FIG. 13C is a scatter plot showing baseline values for human subjects as a function of age, according to at least one exemplary implementation.
FIG. 13D is a scatter plot showing C-reactive protein levels in human subjects as a function of age, according to at least one illustrated implementation.
FIG. 14A shows corresponding baseline versus time following baseline measurements for a subset of human subjects following administration of hypertonic calcium-rich salts targeting the upper respiratory tract of the respiratory tract (FEND), according to at least one exemplified implementation. FIG. 4 is a line graph showing the percentage (%) change in mean exhaled particle count from measurements.
FIG. 14B shows the mean from corresponding baseline measurements versus time following baseline measurements for a subset of human subjects after administration of a nasal saline spray (simply saline), according to at least one illustrated implementation. Fig. 3 is a line graph showing the percentage (%) change in exhaled particle count;
FIG. 14C depicts the percentage change in mean exhaled particle count from the corresponding baseline measurement versus time following the baseline measurement for a subset of human subjects, including an untreated control group, according to at least one exemplified run (% ) is a line graph.
FIG. 15A depicts a first cohort administered hypertonic calcium salt (FEND) targeting the upper respiratory tract and a second cohort administered plain saline to reduce hyperinflammation in accordance with at least one exemplified practice. 2 is a bar graph showing the proportion (%) of study subjects who required intravenous antibiotic or steroid intervention among subjects with
Figure 15B shows a population administered i) a calcium chloride sanitary and/or antimicrobial formulation or composition; and iii) a human control group that was not treated with a salt-based sanitary and/or antimicrobial formulation or composition. is a bar graph showing.
FIG. 16A is a bar graph showing self-reported symptom scores as a function of days of hospitalization and dosing over the first three days of FEND, according to at least one illustrated implementation.
FIG. 16B is a bar graph showing self-reported symptom scores as a function of days of hospitalization and administration over the first three days of plain saline as a control, according to at least one exemplified implementation.
FIG. 16C is a bar graph showing self-reported symptom scores as a function of hospital days without administration of nasal salts, according to at least one illustrated embodiment;

The details of the disclosure are set forth below so that the various implementations can be properly understood. One skilled in the art will readily recognize, however, that the present invention can be practiced without one or more of the specific details, or with other methods, components, or materials. deaf. Other examples include microcontrollers, piezoelectric devices, Peltier devices, power supplies such as DC/DC converters, wireless radios (i.e., transmitters, receivers or transceivers), computing systems including client and server computing systems, and networks. (eg, cellular, packet-switched), as well as other well-known structures associated with communication channels have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments.

Unless otherwise required in this specification and claims, the terms "comprise" and derivatives thereof are to be taken to have an indeterminate inclusive meaning, i.e., "include," but are not limited to. not something.

References to "an embodiment" or "an embodiment" throughout the specification mean that at least one embodiment includes the particular feature, structure, or feature described in connection with that embodiment. means Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in this specification are not necessarily referring to the same embodiment. Moreover, the special features, structures or attributes may be combined in any suitable manner in one or more embodiments.

As used in this specification and the accompanying claims, the singular encompasses the plural unless the context clearly dictates otherwise. Also, the phrase "or" is generally used in its sense to include "and/or" unless the context clearly dictates otherwise.

The title and abstract are for convenience only and do not delineate the scope of the invention or represent embodiments.

In particular, provided herein is the advantageous delivery of one or more salt-based formulations or compositions, particularly calcium-rich physiological salt formulations or compositions, through the nose to the upper respiratory tract, To reduce viral shedding and/or as an antibacterial and/or anti-infective effective against airborne pathogens, e.g. New compositions, systems, methods, and articles of manufacture are described for limiting exposure (eg, deep lung) to toxins).

Nasal administration of physiological salts is believed to be particularly effective in reducing airborne particles from exhaled breath, including submicron aerosolized particles that are not effectively filtered by cloth face masks. For example, nasal application of drug-free, calcium-enriched nasal salts can interact with airway mucus to cleanse the airways of bioaerosols, which can reduce exhaled aerosol particles by up to 99% and exhaled particles in the largest cohort of human subjects. The overall reduction in is about 75%. Nasal application of physiological salts (e.g., calcium chloride; a combination of calcium chloride and sodium chloride), for example, restores the natural surface viscoelasticity of the airway lining fluid, e.g. May reduce mucus breakdown. Most of these airway droplets are submicron, and their reduction lowers the risk of deep lung infection and disease spread, recognized by the WHO and CDC as potential carriers of SARS CoV-2. Nasal administration of physiological salts could be an important addition to current COVID-19 hygiene protocols of mask wearing, hand washing, and social distancing. Nasal administration of physiological salts adds efficacy to the mask in reducing penetration of respiratory droplets into the lungs or reverse osmosis into the environment, and adds a layer of protection when mask wearing is not possible.

In particular, misters or nebulizers that deliver an aerosol with a high concentration of calcium to the site of respiratory droplet formation can be particularly effective. Calcium-rich salt ions can associate with mucins on the surface of airway lining fluid and enhance the resistance of mucus to breakdown. This can advantageously cleanse the airways of respiratory droplets that can carry infections and insoluble environmental contaminants.

A new therapeutic practice of intranasal application of calcium-rich saline aerosol to the upper respiratory tract was proposed. Nasal application of physiological salts and, in particular, calcium-rich salts (e.g., calcium chloride; combinations of calcium chloride and magnesium chloride, and relatively low Application of an aerosol of droplets containing concentrations (eg, 0.1% by weight or less sodium chloride, or a combination of sodium chlorides with no sodium chloride at all) can produce beneficial antimicrobial effects.

In particular, misters or nebulizers that deliver aerosols with high concentrations of calcium to the upper respiratory tract may be particularly effective. A mister or nebulizer may deliver a calcium-rich aerosol with or without other salts that are effective antimicrobial agents and/or with or without other antimicrobial substances.

These salt-based sanitary and/or antimicrobial formulations or compositions are advantageously formulated as or in readily dissolving water droplets. Easily soluble water droplets have a median size range of about 7 microns to about 15 microns, preferably about 10 microns. Thus, easily soluble water droplets are too large for significant penetration into the lungs, but small enough to carry them to the nose and upper respiratory tract. Advantageously, such allow salt-based sanitary and/or antimicrobial formulations or compositions to be delivered to the upper respiratory tract without any discernible delivery to the lower respiratory tract, and unexpectedly successfully inhibit viral shedding. can be suppressed or otherwise significantly reduced. Such can be used to inhibit viral shedding in humans and other animals. Such have other beneficial physiological effects, e.g., to limit exposure (e.g., deep lung) to undesirable airborne contaminants (e.g., smoke and other airborne toxins). may be used additionally or alternatively.

The droplets are delivered as an aerosol and are taken up by the subject through the act of inhalation, for example. The aerosol is, for example, open air (e.g., in a room, outside a door), preferably It may be dispensed (or exhaled) reasonably close to one or more of the individual's facial locations (eg, placed relatively in front of one or more of the subject's noses). Alternatively, the aerosol may be dispensed into an enclosed or partially enclosed volume such as a mask, chimney, tumbler, vial, beaker or other vessel or container. The individual inhales the salt-based sanitary and/or antibacterial active through the nose into the upper respiratory tract, eg nasally and/or nasally, possibly post-nasally. Open air distribution is particularly suitable for treating large crowds, e.g. crowds entering a stadium or other venue, e.g. without the individuals in the crowd touching any objects (e.g. delivery devices or dispensers). obtain.

The salt-based hygiene and/or antimicrobial active loaded droplets described herein can be generated from small reservoirs of less than 100 ML, for example, for individual treatment of subjects. Alternatively, a larger reservoir may be used, for example, when treating a crowd of individuals entering a stadium or other venue or event location.

Salt-based sanitary and/or antimicrobial compositions and formulations may contain one, two or more forms of physiological salt, at least one of which is calcium chloride, which is dissolved in water. be done. Salt-based sanitary and/or antimicrobial compositions and formulations, for example, combine calcium chloride and sodium chloride in a 4× isotonic composition (4.72% CaCl ₂ in 0.31% NaCl) [0.43M CaCl ₂ , 0.05 M NaCl]; or a 2× isotonic composition (1.29 CaCl ₂ in 0.9% NaCl) [0.12 M, 0.15 M NaCl].

Salt-based sanitary and/or antimicrobial compositions and formulations may contain one or more other salts such as potassium chloride and/or magnesium chloride. Salt-based sanitary and/or antimicrobial compositions and formulations contain, in addition to water, one or more essential oils, aromatic oils or flavor extracts (e.g. cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil). , palm oil, fig oil, grapefruit oil, hazelnut oil, honey melon oil, lavender or spike lavender oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise extract, rose oil, and/or linalool-containing oils) and/or solvents (eg, ethanol).

Exhaled aerosol counts are considered not only an indicator of disease progression, but also a marker of disease risk in uninfected individuals. As a diagnostic technique, exhaled aerosol monitoring may be performed.

New Natural Defenses Against Airborne Pathogens Airborne transmission of infectious diseases by very small droplets that are expelled from the human respiratory tract by spontaneous respiration and accumulate in poorly ventilated indoor environments is responsible for a range of infectious diseases including tuberculosis, measles, chickenpox, influenza and SARS. respiratory disease (Yi et al 2007). Recent observations show that the novel coronavirus SARS-CoV-2, carried by small airborne droplets exhaled by a COVID-19 infected person and reported to be stable in aerosol form for more than 3 hours, It is similarly positioned in the family of airborne infections. Evaluation of SARS-CoV-2 as an airborne pathogen reveals the nature of the fight against the COVID-19 pandemic.

While major international scientific efforts to develop medicines and vaccines advance in response to the COVID-19 pandemic, less attention is paid to new ways to preventively combat airborne viral and bacterial threats. has not been paid. Social distancing, hand washing, and wearing a face mask, each effective and necessary, do not impede the transmission of airborne pathogens within droplets less than 1 μm in diameter. Such small particles are not only too small to be effectively filtered by conventional masks, but also too small to be sedimented by gravity within the 2-meter threshold of social distancing.

Submicron droplets, which can be the bulk of the particles, are expelled from the mouth and nose during natural breathing. Submicron particles travel through the respiratory system either through the necking of airway lining fluid that occurs with lung inflation and deflation, or the rapid movement of air through the upper airways that occurs during spontaneous respiration, coughing, sneezing, and vocalization. come out from Small droplets expelled from infected lungs, whether at high or low concentrations in the respiratory tract, carry viral and bacterial pathogens and toxins into the environment and facilitate the spread of disease. When this ejection of droplets occurs in the upper respiratory tract, it can facilitate the movement of pathogens and toxins to the deep lung, eg, autoinfection.

Saline delivery to the respiratory system has been observed to reduce exhalation of these very small particles. This decrease is due to electrostatic interactions between salt cations and mucin and mucin-like proteins on the surface of airway lining fluid. They increase the surface viscoelasticity of the airway lining fluid and reduce the formation of airborne droplets. Calcium chloride, much more than sodium chloride, has been found to increase the surface elasticity of airway lining fluids and may further promote a more substantial inhibition of airborne particle production in the airways, On the other hand, enhanced surface plasticization also further resists pathogen penetration through the mucus layer and strengthens its biophysical barrier against infection.

Calcium and sodium salts appear to have antimicrobial properties as well. High concentrations of extracellular calcium promote secretion of β-defensin 2 from nasal epithelial cells, as can be achieved by aerosol delivery of calcium salts. Human β-defensin 2 is an endogenous antimicrobial peptide that binds to the receptor-binding domains of many viruses, including coronaviruses, and promotes the expression of antiviral and immune-inducing molecules as well as chemokine recruiters in leukocytes. Human β-defensin 2 has been shown to be effective as an antiviral adjuvant due to its binding to the spike protein of MERS CoV, and mouse β-defensin 4-derived peptides have been shown to be effective against SARS CoV-1. showed activity.

Chloride salts have been shown since the 1960's to reduce viral replication. Chloride ions promote antiviral activity by intracellular induction of hypochlorous acid, the active ingredient in bleach. Chloride salts induce the innate immune response of epithelial cells in the presence of sodium chloride. Sodium hypochlorite, the sodium salt of hypochlorous acid, has particularly demonstrated effectiveness as a disinfectant against coronaviruses. High concentrations of chloride are delivered to the nasal epithelium via hypertonic saline and have been shown to reduce viral infections associated with the common cold. In an open-label, randomized, controlled study of 68 subjects with common cold infections, including rhinoviruses, coronaviruses, enteroviruses, and influenza A virus, 2-3% hypertonic saline was administered twice daily. Eight intranasal doses (median of 3 doses/day) significantly reduced disease duration as well as use of over-the-counter medications, household transmission, and viral shedding. Nasal administration of 3.5% hypertonic seawater has similarly shown efficacy indications against cold symptoms in other human clinical trials.

Described herein are various salt compositions that incorporate at least two ions that are abundant in human tissue: calcium and chloride, and optionally the tertiary ion sodium, which are used in hygiene applications. It may also, for example, address the need for a wide range of prophylactic and anti-infective defenses against respiratory viral and bacterial infections. Without wishing to be bound by theory, the inventors believe that an aerosol combining calcium and optionally a sodium salt reduces bioaerosol formation in the lungs and nasal passages while reducing the mucus lining to protect against infection. hypothesized to improve the barrier function of Considering the hygienic practice of nasal saline irrigation, we evaluated nasal delivery of these salines with a specially designed nasal mist as a practical, effective and safe personal hygiene intervention complementary to masks. did. This may prove particularly useful for immediate combat with the current COVID-19 pandemic, but may also be useful against other airborne pathogens and/or toxins. .

Results Nasal Delivery Device A handheld nebulizer (Nimbus®) device was designed to be able to deliver a salt-based sanitary and/or antimicrobial formulation or composition nasal dose of approximately 1-2 mg CalCl ₂ . The nebulizer device uses an integrated vibrating mesh with 6 μm pore size to produce an aerosol cloud with an optimal particle size distribution for intranasal delivery through natural nasal inspiration when the device is tipped over. did. From the particle size distribution of the aerosol cloud, the median volume particle size was 9-10 μm, the optimal size for nasal and upper respiratory tract deposition of the aerosol after natural tidal inspiration through the nose and the anterior part of the nose. We find that the distribution of deposition from the to the posterior is relatively uniform (Calmet et al., 2019). The particle size distribution is significantly smaller than that produced from a standard nasal pump spray (Figure 6B).

Upon tipping (FIG. 1A), the Nimbus® nebulizer device produces 57 mg +/-2 mg for 10 seconds of actuation, after which power is turned off until tipping. The Nimbus® nebulizer device fills an empty 6-ounce glass with a cloud (or cloud) for an internally programmed 10 second period of device actuation, then clouds directly from the glass into the nose. It is designed to deliver a controlled dose of approximately 33 mg (ie, 1.56 mg CalCl ₂ or 0.43 mg CalCl ₂ ) by inhaling 10 mg CaCl 2 (FIG. 1B). Uncontrolled dosing can also be achieved by creating a cloud in front of the nose and direct natural deep nasal inspiration (Fig. 1B).

Compared to our observations of the efficacy of salt-based sanitary and/or antimicrobial formulations or compositions for pulmonary delivery, the efficacy of salt-based sanitary and/or antimicrobial formulations or compositions for suppressing exhaled aerosol particles after nasal administration It was decided to follow a human volunteer study using the Nimbus® nebulizer device to evaluate the efficacy of a formulation or composition.

Human Breath Bioaerosol Study: Nasal Administration Ten healthy volunteers were recruited at St Augustine, Massachusetts and Boston, Florida. Each consented to participate in a nasal saline hygiene test for several hours. Five of these were over 65 years old (70, 75, 82, 83, 88 cases) and 5 were under 65 years old (30, 40, 59, 60, 63 cases). Subjects with severe respiratory illness were excluded from the study, but two of the subjects (ages 30 and 63) were smokers.

All subjects began the study by breathing into a device that measures exhaled aerosols. Following baseline evaluation of exhaled aerosol particle counts, two deep nostrils of a 4× isotonic composition of 1.29% CaCl ₂ and 0.31% NaCl dissolved in water were administered via a Nimbus® nebulizer device. I took a breath. After dosing, subjects breathed into an airborne particle detector for intervals up to 6 hours after dosing. Subjects also self-administered a commercially available (isotonic sodium chloride) plain saline wash spray (CVS Nasal Saline). Following the placebo-controlled nasal administration, subjects breathed into the air-borne particle detector for intervals of up to 2 hours.

Baseline breath particles per liter per subject age are shown in Figures 2A and 2B. Two of the 10 subjects in the elderly (>65) group exhaled significantly more particles (24,088+/9413 and 7180+/1250) per liter of air (Fig. 2A), whereas the other 8 Humans (FIG. 2B) ejected approximately 10-1200 particles per liter. In the latter group, two (ages 30 and 63) were smokers. There is a strong correlation between the number of exhaled particles and age, with the 65+ age group exhaling an average of 6641 particles/liter and the <65 years old group exhaling an average of 440 particles/liter. In all subjects, more than 95% of baseline exhaled particles were less than 1 micrometer in size, with the majority less than 500 nm.

After administration of salt-based sanitary and/or antimicrobial formulations or compositions, exhaled particle counts decreased by several hours, as shown in FIG. Statistically significant (p<0.05). The duration of effect continued until the last data point several hours (2-6) after dosing for all subjects except Subjects B and E, who were each very small particle producers. Administration of the plain saline control had a slight inhibitory effect on exhaled particles in two of the subjects in the first hour after administration, but no inhibitory effect was observed in the other subjects ( 4A-4I).

Bioaerosol reduction ranged from as low as 45% (subjects age 75) to as high as 99% (subjects ages 83 and 70), using lowest post-dose exhaled particle counts as a measure of inhibitory efficacy. and the overall suppression of aerosols in the herd (99%) was associated with aerosolized salt-based sanitary and/or antimicrobial formulations in superproductive individuals (subjects ages 83 and 70) or Mainly related to the remarkable effect of the composition.

Discussion Hypertonic calcium chloride and sodium chloride solutions delivered to the respiratory system appear to have potential as both hygienic and therapeutic biodefenses against airborne pathogens. Hygienically, these physiological salts coat the airway lining fluid surface to break up and remove submicron bioaerosol droplets that are not effectively captured by the mask. Potentially by enhancing natural immunological defenses--by enhancing the airway lining fluid barrier function and promoting the secretion of β-defensin 2 from the nasal and bronchial epithelium--these salts are antibacterial. Drugs may also act therapeutically for prophylaxis or treatment.

Although these results suggest that combinations of calcium and sodium chloride salts may be therapeutically useful against bacterial and viral infections, including influenza, rhinovirus and pneumonia, these results suggest that COVID-19 In the use of calcium chloride salt formulations and compositions in combating any airborne disease, including 19, it points to the immediate hygienic value of cleansing the airways of small airborne droplets that carry airborne infections. do.

In a group of 10 healthy human subjects, nasal inhalation of a salt-based sanitary and/or antimicrobial formulation or composition of 1.29% CaCl ₂ and 0.31% NaCl dissolved in water resulted in lower The finding that between 45% and 99% of exhaled particles are reduced by aerosols that are too large to penetrate the respiratory tract (Figures 8 and 4A-4I) indicates that the upper respiratory tract is the major source of exhaled bioaerosols. Suggest. High-velocity air currents generated during natural respiration in the trachea and main bronchi disturb the surface of the airway lining fluid on the way of wind passing over the ocean, producing sea fog. Such a phenomenon is highly sensitive to compositional variations in the underlying fluid, making exhaled bioaerosol a sensitive measure of airway lining fluid and introducing intra- and inter-subject variability.

In the present study, application of salt-based sanitary and/or antimicrobial formulations or compositions substantially eliminated exhaled particles, most of which were less than 1 μm in size. Particles in the 300-500 nm range were most prevalently observed in the subject's breath, suggesting that such particles are too small to be deposited in the lungs by gravity or inertia, and too large once generated. can be explained by the fact that it is not deposited by diffusion. These are submicron particles that are most likely to remain suspended in the atmosphere essentially indefinitely. Perhaps most important with respect to their ability to transmit infection and to deposit on surfaces, including infected or naive individual airways, particles in the 500-1000 nm range, which are a significant fraction of superspreader individual exhaled particles. is. These particles are also substantially eliminated by salt-based sanitary and/or antimicrobial formulation or composition treatments.

In the test, most of the airborne particles were exhaled from two of the ten "super-productive" individuals. This super-production of bioaerosols drives the phenomenon of super-spreaders (Stein 2015). COVID-19 superspread events have been reported in China (so-called patient 31), India (Punjab outbreak), South Korea and many other regions and are suspected to be the main mode of transmission of the disease. Among the key correlates of superpropagation are immune suppression and infected lungs—two particular vulnerabilities of the oldest. In fact, older subjects in this study exhaled more particles than younger subjects, suggesting that while older subjects are the most vulnerable to COVID-19 infection, they are also the subjects most likely to spread the disease. and underscores the extreme-risk seniors facing today in nursing homes.

As nasal hygiene, salt-based hygiene and/or antimicrobial formulations or compositions are easy to administer (Fig. 1B), rapid (one or two deep nasal breaths), long (maximum number of particles lasting at least 6 hours) in those who expire It can be easily administered to individuals in indoor environments where they may encounter others, including hospitals, nursing homes, prisons, schools, offices, factories, stadiums, restaurants, and art galleries. Salt-based as an "invisible mask" supplement to traditional masks administered prior to close encounters with others in public and private spaces to clear the air of small particles that masks do not block. The use of sanitary and/or antimicrobial formulations or compositions is considered a sensible addition to current hygiene practices in the face of the COVID-19 pandemic.

Further studies may be conducted to evaluate the results of calcium-enriched saline nasal hygiene on airborne infection and transmission rates in environments with high risk of COVID-19 and other airborne diseases. The therapeutic potential of these nasally and pulmonary delivered salts should also be explored beyond the in vitro and animal studies reported herein.

FIG. 1A shows a delivery device 100 for delivering an aerosol 102 of a salt-based sanitary and/or antimicrobial formulation or composition into an unconfined space or volume to be inhaled by a subject, according to at least one illustrated implementation. is an isometric view of the . Tipping of the Nimbus® nebulizer device with respect to the Earth's gravitational axis actuated the actuator to vibrate the mesh, thereby generating an aerosol cloud for administration.

FIG. 1B illustrates using a delivery device for delivering an aerosol of a salt-based sanitary and/or antimicrobial formulation, or into either unrestricted or free space or volume, or Various sequential actions performed using a delivery device to deliver to a restricted space or volume (e.g., mask, chimney, tumbler, vial, beaker, or other container or container) that is inhaled by a subject 1 is an exemplary diagram of the . Salt-based sanitary and/or antimicrobial formulations or compositions contain an aerosol cloud in a partially enclosed environment such as a mask, chimney, tumbler, vial, beaker or other vessel or container by), for example, in an unrestricted environment, such as in front of the subject's nose, by a Nimbus® nebulizer device with deep nasal inhalation.

As shown in FIG. 1B, a reservoir 104 containing a salt-based sanitary and/or antimicrobial formulation or composition 106 (eg, CaCl ₂ ) dissolved in water (eg, distilled water) is provided at 1 . At 2, the reservoir 104 is then connected to the dispenser portion 108 of the Nimbus® nebulizer device in a generally upright (with respect to the axis of gravity) orientation. The dispenser portion 108 of the Nimbus® nebulizer device 100 can include a housing, a mesh, an actuator coupled to driveably vibrate the mesh at a desired frequency, and/or drive circuitry. The drive circuitry can include, for example, accelerometers, earth magnetic field sensors, level sensors, and/or gyroscopes, which sense the tipping of the Nimbus® nebulizer device with respect to the axis of gravity and actuate the actuators. . The drive circuit can include, for example, a timer that deactivates the actuator after a defined period of time to control the dosage of dispensed salt-based sanitary and/or antimicrobial formulation or composition.

At 3, a Nimbus® nebulizer device 100 is placed proximate to a subject's face and/or nose 110 and tilted with respect to the axis of gravity to deliver salt-based hygiene and/or antimicrobial as an aerosol 102. The formulation or composition is dispensed (or expelled) into an unrestricted or free space or volume 112 that is not contained by the enclosure. In response, the drive circuit activates the actuators to vibrate the mesh to deliver a salt-based hygienic and/or antimicrobial formulation or composition as an aerosol proximate the nose 110 of the subject. (eg, nasally) for inhalation by the subject and dispensed into the upper respiratory tract.

Alternatively, at 4, the Nimbus® nebulizer device 100 is positioned proximate to the container or opening of the container 114 and tipped against the axis of gravity to deliver salt-based sanitary and/or antimicrobial as the aerosol 102. A space or volume restricted or at least partially enclosed by an enclosure (e.g., a mask, chimney, tumbler, vial, beaker, or other container or vessel 114) that contains a sexual formulation or composition. distribute to In response, the drive circuit activates the actuator to vibrate the mesh and dispense the salt-based hygienic and/or antimicrobial formulation or composition as an aerosol 102 into the container or container 114 . At 5, the container or vessel 114 is placed in the face of the subject for inhalation by the subject through the nose 110 (e.g., nasally and/or nasally) and into the upper airway of the airway. and/or located proximate the nose 110 .

As used herein, a confined or partially confined or restricted volume means an unconfined or unrestricted volume (e.g., 100 feet ³ or about 2.8 m ³ of Refers to a vessel-sized volume (eg, on the order of 1 foot ³ or about 28316 cm ³ ) compared to a room-sized volume of the order of 1 foot 3 .

Figures 2A and 2B show breath particle measures from 10 human volunteers prior to salt-based sanitary and/or antimicrobial dosing. Exhaled particles per liter of air are shown in three size distributions: 300-500 nm, 500-1000 nm and 1000-5000 nm. In particular, FIG. 2A shows results from two of the human subjects (ages 63 and 70) who exhaled over 25,000 and 7000 particles/liter, respectively, the majority of these particles being between 300-500 nm. and the majority of the particles are between 500 nm and 1000 nm. Figure 2B shows results from eight other individuals who breathed an average of several hundred particles per liter.

FIG. 3 shows a measure of exhaled particles from each of ten human volunteers after salt-based hygienic and/or antimicrobial dosing. In all cases, the most “superproductive” subjects (63 and 70 cases) had >99% reduction in total exhaled particle counts 6 hours after salt-based hygienic and/or antibacterial nasal inspiration, While the effect is dramatically significant, a statistically significant suppression of exhaled aerosol is observed.

Figures 4A-4I are graphs showing measurements of exhaled particles per subject after salt-based hygiene and/or antimicrobial administration compared to placebo controls. Comparing the effects of salt-based sanitary and/or antimicrobial formulations or compositions and isotonic saline (CVS Saline Spray) dosing on exhaled aerosol counts, all exhaled particles (all sizes) up to 1 hour after dosing Shown with standard error bars, specifically for the subjects represented in Figures 4D and 4G, the saline control shows significant suppression, while for the subjects represented in Figure 4F, it shows significant amplification. . In all cases, aerosolized treatment with salt-based sanitary and/or antimicrobial formulations or compositions increased exhaled aerosol counts compared to controls when comparisons were made between the nearest time points of measured counts. (p<05). The indicated human subject ages are (A) 83 (B) 40 (C) 70 D) 88 (E) 76 (F) 59 (G) 63 (H) 75 (I) 30.

FIG. 5 is a schematic diagram showing a portion of a nebulizer delivery device 1000 according to at least one illustrated implementation. The nebulizer delivery device 1000, according to at least one illustrated implementation, may or may not take the form of a nebulizer 1002 having one or more actuators 1004 and a control subsystem 1006, or other electronics. If not, it can be included.

The nebulizer 1002 can include one or more mesh screens 1008, e.g., metal mesh screens, e.g. The nebulizer 1002 includes piezoelectric elements 1012, solenoids 1014 physically coupled to move the mesh screen 1008 along at least one axis in response to signals from the microcontroller to dispense the aerosol into the chamber. , or one or more of the electric motors 1016 . In some implementations, actuators are physically coupled to mesh screen 1008 via one or more mechanical (eg, elliptical gears) or magnetic transmissions. A nebulizer can, for example, vibrate a screen at ultrasonic frequencies to cause dispersion of the scent medium. The transducer may oscillate at a frequency of approximately 112 KHz±10 KHz, which is sufficient to atomize the fluid held within the fluid reservoir. As will be appreciated by those skilled in the art, the vibration frequency may be geometry dependent and may be tuned to the harmonics of each piezo element design employed as an actuator. The oscillation frequency of such transducers can be increased or decreased depending on the properties of the fluid or other material held within the fluid reservoir. The fluid can, for example, have a viscosity of about 1.25 mPa at room temperature. In at least some implementations, the transducer can form an annular ring with a metal mesh contained within a central portion of the transducer. The metal mesh screen 1008 can take the form of, for example, stainless steel or various metals of 304 or 316 grades, the 316 grade being particularly resistant to corrosion. Metal mesh screen 1008 may be provided as a foil. In some implementations, the metal mesh screen 1008 may be fluidly coupled to the fluid reservoir via capillaries, thereby allowing low fluid flow from the fluid reservoir to the metal mesh screen 1008. provide a route. Thus, the fluid may be transported, for example, via capillary action to the metal mesh, where it is atomized into a vapor or, more preferably, an aerosol as a result of vibration of the transducer. In some implementations, the metal mesh screen 1008 can provide a filter to prevent large size molecules from being released as part of the vapor or, more preferably, the aerosol exiting the dispenser. Accordingly, the metal mesh screen 1008 may have mesh openings that are approximately 6 microns in size. In some implementations, mesh openings can be less than 6 microns wide (eg, 5 microns, 4 microns, 3 microns, or 2 microns). In some implementations, mesh openings can be greater than 6 microns wide (eg, 7 microns, 8 microns, 9 microns, or 10 microns). Preventing larger molecules from being dispensed may provide a better user experience by reducing the likelihood that the vapor, or more preferably the aerosol, will irritate the user.

Nebulizer 1002 can include one or more radios 1018 , transducers or sensors 1020 , and switches 1022 communicatively connected to control subsystem 1006 .

Control subsystem 1006 may include, for example, one or more microcontrollers 1024, microprocessors, field programmable gate arrays, and/or application specific integrated circuits. Control subsystem 1006 may include, for example, one or more non-temporary storage media 1026 storing at least one processor-executable instruction or data, which processor-executable instruction or data is processed by microcontroller 1024 . When executed, it causes the microcontroller 1024 to control the operation of the device 900, eg, in response to one or more inputs. For example, a microcontroller can receive signals from one or more of radio 1018, transducer or sensor 1020, and switch 1022 and control the operation of nebulizer 1002 in response. For example, the control subsystem may cause the nebulizer to dispense or disperse the scent medium in response to a first input, and cause the nebulizer 1002 to dispense or disperse a salt-based antibacterial and/or anti-infective formulation or composition in response to a second input. Dispensing or distributing the material can be stopped. Inputs may include user manipulation of switches, vessel positioning or orientation by the user, or wireless commands from a wireless or remote controller.

Nebulizer delivery device 1000 may include, for example, one or more switches and/or sensors. The switches and/or sensors may be communicatively coupled to the microcontroller and operable to generate signals that cause the microcontroller to operate the actuators accordingly. The switches may include, for example, any one or more of contact switches, momentary contact switches, rocker switches, and the like. The sensors can include, for example, one or more of any of the following: The device can include, for example, one or more sensors, such as 1, 2, or 3 axis accelerometers, PIR motion sensors, inductive sensors , capacitive sensors, and reed switches. The switches and/or sensors are operable, for example, to cause the microcontroller to generate signals that activate the actuators in response to at least one nebulizer delivery device 106 coupled to at least one of the docks. The switch (nebulizer) and/or sensor(s) are operable, for example, to respond to the presence or absence of a vessel relative to the base and to generate signals that cause the microcontroller to operate the actuators in response to the presence or absence of a vessel relative to the base. obtain. The switches and/or sensors may, for example, be responsive to the position or orientation of the vessel and operable to generate signals that cause the microcontroller to operate the actuators in accordance with the orientation of the vessel. The switch and/or sensor can be part of at least one nebulizer delivery device, for example.

Nebulizer delivery device 1000 may include a transducer communicatively coupled to operate the nebulizer. A transducer is, for example, one or more radios (e.g., cellular transceiver, WI - FI transceiver, Bluetooth transceiver). The transducer may include one or more receivers, such as an infrared receiver that receives infrared light signals from the remote control.

Activation can be synchronized with delivery of audio, video, or audiovisual media. For example, a smartphone or digital assistance (eg, Amazon Alexa®, Google Home®, Apple HomePod®) can cause activation of nebulizer 1002 .

A suitable microcontroller may take the form of an 8-bit microcontroller with in-system programmable flash memory, such as those available from Atmel Corporation under the designation ATMEGA48/88/168-AU. The microcontroller executes programs stored in its memory and sends signals to control various other components such as, for example, valves. The control signal may be, for example, a pulse width modulated (PWM) control signal, particularly when controlling an active power supply. Otherwise, the control signal can take any of a wide variety of forms. For example, a microcontroller can actuate a valve or actuator 1004 simply by completing the respective value or circuit that powers the actuator 1004 .

Nebulizer delivery device 1000 can optionally include a visual indicator (not shown) to indicate when nebulizer delivery device 1000 is activated or turned on. A single light emitting diode (LED) may be used, but the visual indicator may take any of a variety of forms. The LED can emit one, two, or more nebulizer colors. A visual indicator may also indicate other information or conditions, for example, a visual indicator may flash in response to the occurrence of an error condition. A pattern of flashes (eg, number of flashes in succession, color of flashes, number and color of flashes in succession) can be used to indicate which of several possible error conditions have occurred.

In some implementations, nebulizer delivery device 1000 is motorized by one or more batteries that can provide power for the vibration of actuator 1004 . Batteries can be small and lightweight, such as batteries used in small electronic devices (such as hearing aids). In some implementations, the battery is at least partially embedded within the nebulizer delivery device. In some implementations, the battery is selectively removable and replaceable, such as when the battery no longer provides sufficient charge to operate the nebulizer delivery device 106 . One or more photovoltaic panels and associated photovoltaic panels capable of converting light into energy that can be used to operate the nebulizer delivery device 106, an array of supercapacitor or ultracapacitor cells, or an array of fuel cells. Other types of power sources can be provided, such as component power sources.

Although not shown, one or more cartridges can carry the dispensed salt-based antimicrobial and/or anti-infective formulations or compositions. The cartridge is removed by the fragrance medium reservoir of the nebulizer delivery device to supply the solution of salt-based antibacterial and/or anti-infective formulation or composition to the nebulizer for dispersion, e.g., as a spray of droplets or an aerosol. It is sized and dimensioned to be as acceptable as possible. The cartridge can be made of plastic. A single-use cartridge may, for example, contain a single dose of a substance that is dispensed and stored in liquid form. Alternatively, large reservoirs can be used at large venues and events.

The cartridge can form a fluid reservoir and can be constructed from polymers, elastomers, or other lightweight, durable materials that can be used to hold liquids. The cartridge may be formed from one or more plastics, such as ABS or polycarbonate plastics. Plastic can be injection molded or vacuum formed to form the cartridge. The type of material or process used to form the cartridge from the material should not be considered limiting. In some implementations, the cartridge contains one or more salt-based salts as fluids or other materials (e.g., powders, gels, colloidal suspensions) carrying active agents (e.g., calcium chloride and sodium chloride). It may contain an internal cavity forming a fluid reservoir that may be used to hold and contain an antimicrobial and/or anti-infective formulation or composition. In some implementations, for example, the fluid reservoir can be sized and dimensioned to hold up to 100 mL of fluid. In some implementations, the fluid reservoir can hold less than 100 mL (eg, 5 mL, 10 mL, 20 mL, 40 mL, or 50 mL), for example, the maximum amount of fluid used to form a single dose. It can be sized and dimensioned to hold. The fluid is any salt-based antibacterial and/or anti-infective formulation or composition or composition that is released when the fluid passes into a vapor or, more preferably, an aerosol and is released. It can be liquid or other material. The cartridge can include openings that form part of a fluid communication path for transferring fluid from the fluid reservoir to the nebulizer for conversion to a vapor or, more preferably, an aerosol. The vapor, or more preferably the aerosol, can advantageously contain readily soluble water droplets having a median size range of about 7 microns to about 15 microns, more preferably about 10 microns. Thus, easily soluble droplets are too large for significant penetration into the lungs, while small enough to be carried through the nose to the upper respiratory tract.

6A-6F illustrate a hand-held Nimbus® nebulizer delivery device 2100 for generating and delivering a cloud of an aerosolized salt-based antibacterial and/or anti-infective formulation or composition in aerosol form. FIG. 2 shows various figures (e.g., suspensions of droplets in air containing CaCl ₂ and/or MgCl ₂ salts in water of droplets of enumerated concentrations, each with or without NaCl). .

A handheld nebulizer (Nimbus®) operates based on a vibrating mesh powered by two replaceable AAA batteries. The device consists of a head containing a piezoelectric vibrating mesh and an on/off trigger, and a base or 1 oz. (30 mL) Vials that can be filled with salt-based sanitary and/or antimicrobial formulations or composition solutions. Nimbus® vials are removable, made of glass or plastic, filled with sterile solution, and discarded when empty. A 4-place balance (0.1 mg precision) was used with a hand-held nebulizer to assess delivered dose. The Nimbus® was inverted and the cloud dispensed into a 6 oz. jar covered with a disk with a hole to release the cloud into the glass container. After 10 seconds, cloud formation stopped, the Nimbus® was removed, the disc was removed, and the glass was weighed. The "exit dose" (n=5) results involved measuring the entire 10 second discharge through the coaster into the jar and immediately capping the coaster hole. The total emitted mass from the device was measured as 57.0±2.1 mg. About 22.1±1.5 of the dose deposited on the glass wall, or about 39% of the emitted dose. Nasally delivered dose was evaluated by 2 users (n=5) affecting a single nasal inhalation from the glass after filling. Results of 22.6 mg and 23.4 mg, respectively, suggest reproducible delivery of the solution and target nasal dose range.

Device 2100 can include any of the features of any of the other devices described herein and can be used in combination with any of the other devices described herein. As illustrated in FIG. 6A, the delivery device 2100 includes a base 2102, which may be transparent, which is used to hold the salt-based antimicrobial and/or anti-infective formulation or composition in liquid form. Including hollow containers or tanks or vials, optionally having a volume or capacity of less than 100 mL. Base 2102 also includes an upwardly extending hollow conduit, tube, or pipe 2116 through which salt-based antimicrobial and/or anti-infective formulations or compositions can be poured from base 2102 in liquid form. can. The outer surface of conduit 2116 includes a set of threads.

Delivery device 2100 also includes an upper or upper or main body 2104 that contains the hollow housing and electronic and mechanical components of delivery device 2100 . Such components include printed circuit board 2200 and associated components coupled thereto, a pair of batteries 2106, hollow conduits, tubes or pipes 2108, 3 microns, 4 microns, 6 microns, 20 microns, or 3-20 microns. It includes a piezoelectric device 2110 which may include or be physically coupled to a mesh screen having a micron mesh size, and an inner cover 2112 and an outer cover 2114 which may be transparent or translucent. The housing of body 2104 can be opaque or translucent and can have a particular color such as red, orange, yellow, green, blue, purple, brown, black, or white. The inner cover 2112 can have an appearance that matches the appearance of the housing of the body 2104 . In particular, the inner cover 2112 can be opaque or translucent if the housing of the body 2104 is translucent, and if the housing of the body 2104 is translucent, it can be colored red, orange, yellow, green, blue, It can have a particular color that matches that of the body 2104 housing, such as purple, brown, black, or white.

Conduit 2108 includes a relatively wide top portion, a relatively narrow middle portion, and a relatively wide bottom portion sized to extend around conduit 2116 of base 2102 . The inner surface of the bottom end portion of conduit 2108 includes threads complementary to those of conduit 2116 such that conduits 2108 and 2116 can be threadedly engaged and thereby coupled together. When conduits 2108 and 2116 are coupled together, liquid salt-based antimicrobial and/or anti-infective formulations or compositions can flow through conduit 2116 from base 2102 into conduit 2108 . The relatively wide upper end of conduit 2108 allows the liquid salt-based antimicrobial and/or anti-fouling formulation or composition to flow through conduit 2108 from its lower end to the piezoelectric device contained at its upper end. Sized and configured to accommodate the piezoelectric device 2110 at the upper end of the conduit 2108 so that it can flow.

Conduit 2108 also includes a pair of flanges 2118 connected to opposite outer sides of the central portion of conduit 2108 and extending laterally outwardly from the respective sides and in aligned directions along the length of conduit 2108 . Flanges 2118 each include a recess or cradle shaped and configured to receive a portion of one of batteries 2106 so as to partially restrict batteries 2106 when device 2100 is assembled. The inner cover 2112 comprises a generally circular or disc-shaped main body portion and a hollow, frusto-conical portion 2120 extending upwardly from the main body portion. The body portion of inner cover 2112 includes a pair of openings, apertures 2122, extending therethrough. Each of the openings 2122 is sized and configured to receive a portion of one of the batteries 2106 to partially confine the batteries 2106 when the device 2100 is assembled. The outer cover 2114 includes a generally circular or disc-shaped main body portion and an opening or aperture 2124 extending through the main body portion. Aperture 2124 is sized and configured to fit snugly around a portion of the outer surface of cone-shaped portion 2120 of inner cover 2112 when device 2100 is assembled.

6B, 6C, and 6D illustrate perspective, side, and cross-sectional side views of delivery device 2100, respectively. 6E and 6F illustrate two different side views of delivery device 2100 with the housing of body 2104 removed to reveal the internal components of body 2104. FIG.

7A-7D illustrate printed circuit board 2200 of delivery device 2100 with associated components coupled thereto. FIG. 7A is a rear view of a printed circuit board 2200 that includes an LED 2202 physically and electrically coupled to its rear surface, which emits light when the delivery device 2100 is aerosolized. Lighting or so as to light up when generating a salt-based antimicrobial and/or anti-infective formulation or composition or a cloud of a salt-based anti-microbial and/or anti-infective formulation or composition in the form of an aerosol operable, indicating that the delivery device 2100 is operable to turn off when not producing a cloud of aerosolized salt-based antimicrobial and/or anti-infective formulation or composition. The LED may be useful to the user of the device 2100 because when the LED is lit, the user can be sure that power is being supplied to the printed circuit board 2200 . 22A also shows that the back surface of printed circuit board 2200 is physically and electrically coupled to two metal springs 2204, each of which acts as a contact for and partially supports one of batteries 2106. or arranged and configured to cradle. One of the springs 2204 can act as a positive contact and the other of the springs 2204 can act as a negative contact for the battery 2106 so that the batteries 2016 are placed in the device 2100 with opposite polarities. .

FIG. 7B is a side view of printed circuit board 2200, with the rear surface of printed circuit board 2200 also physically and electrically coupled to a plurality of gold pins 2208 to which fluid sensors may be physically and electrically coupled. indicates FIG. 7C is a front view of a printed circuit board 2200 where the front side of the printed circuit board 2200 can include electrical connectors 2212, which can be JST connectors, to allow an operator to print other electronic devices such as piezoelectric device 2110. Physically and electrically coupled to the circuit board 2200, the printed circuit board and other associated components coupled thereto communicate (e.g., transmit signals) with such other electronic devices, including the piezoelectric device 2110. or receive signals from). FIG. 7C also shows that the front surface of printed circuit board 2200 is physically and electrically coupled to tilt sensor 2206, which detects when the ball moves and device 2100 is tilted. It may include an accelerometer or ball tilt switch that connects pins to complete an electrical circuit, and a plurality of capacitors 2210 for storing electrical energy. FIG. 7D is a perspective view of printed circuit board 2200 showing a perspective view of printed circuit board 2200 coupled with relevant components. Figures 7E-7G show the printed circuit board 2200 without the associated components attached.

6A-6F, the rear portion of the printed circuit board 2200 shown directly in FIG. 7A faces toward the center of the conduit 2108 and delivery device 2100, while shown directly in FIG. 7C. The front of printed circuit board 2200 faces away from the center of conduit 2108 and delivery device 2100 . In some implementations, printed circuit board 2200 receives power from a power supply between 2.0 and 3.4 volts DC and delivers power to a load at 65 volts peak-to-peak at 140 KHz. 7H shows a front view of an alternative shape and configuration of printed circuit board 2200. FIG. 7A-7H show some examples of possible dimensions of printed circuit board 22, using numbers in millimeters. It will be appreciated that the specific dimensions provided in these figures are merely examples of possible suitable dimensions.

To operate the delivery device 2100, the user fills the base 2102 with a salt-based antibacterial and/or anti-infective formulation or composition in liquid form, such as by screwing or screwing the base 2102 onto the body 2104. Then the device 2100 can be assembled without the battery 2106 and the outer cover 2114 . The user then inserts the battery 2106 into the device 2100 through the opening 2122 in the inner cover 2112 so that the battery rests partially in the cradle by the recess in the flange 2118 and the bottom terminal of the battery 2106 engages the spring 2204 . contact can be made. The user can then couple the outer cover 2114 to the rest of the device 2100 , such as by screwing or pressing the outer cover onto the upper end of the body 2104 . The underside of the outer cover 2114 can include a strip of conductive material, such as metal, that engages the upper terminals of the batteries 2106, the upper terminals of one of the batteries 2106, and the upper terminals of the batteries 2106. can be electrically coupled to the other terminal of the

The user can then lift and tilt the device 2100 such that fluid flows from the base 2102 through the conduit 2108 to the piezoelectric device 2110 under gravity. Once the user tilts the device 2100 to, for example, dock with a primary container, the tilt sensor 2206 can generate and transmit a signal indicating that the device 2100 has been tilted. Additionally, once the fluid flows through the piezoelectric device 2110, the fluid may contact the fluid sensor coupled to the pin 2208 and generate and transmit a signal indicating that the fluid has reached the fluid sensor. Additionally, the device 2100 can include a pressure sensitive switch on its bottom surface that can generate and transmit a signal that the device 2100 is picked up when the device 2100 is picked up from a flat surface. In some implementations, device 2100 does not include manually operated switches or buttons and does not receive input from the user other than one, two, or three of the signals described above.

Upon receiving any one, any two, or all three of such signals, the device 2100 activates the piezoelectric device 2110 to convert scent media in liquid form to aerosolized salt-based scents in aerosol form. A cloud of antimicrobial and/or anti-infective formulations or compositions or salt-based anti-microbial and/or anti-infective formulations or compositions can begin to form. As the device 2100 is tilted sideways or upside down, the cloud of aerosolized salt-based antimicrobial and/or antimicrobial formulation or composition or salt-based antimicrobial and/or antimicrobial formulation or composition , can exit the device 2100 through the hollow conical portion 2120 and be distributed in free space for direct consumption by the user or pouring into another container or container for subsequent consumption by the user. can be done. In some implementations, the device 2100 includes an internal timer to automatically turn off or deactivate the piezoelectric device 2110 to release the aerosol form after a period of about 5, about 10, about 15, or about 20 seconds. aerosolized salt-based antimicrobial and/or anti-infective formulation or composition or cloud of salt-based anti-microbial and/or anti-infective formulation or composition. In other implementations, the device 2100 is placed in an aerosol form of an aerosolized salt-based antibacterial and/or anti-infective formulation or We continue to operate and produce compositions or salt-based antibacterial and/or anti-infective formulations or compositions.

When the fluid in the base 2102 is exhausted, the user can remove the base 2102 from the body 2104 of the device 2100 and remove the base 2102 from more of the salt-based antimicrobial and/or antifouling formulation or composition in fluid form. , the base 2102 can be screwed or screwed back into the body 2104, and use of the device 100 can then be resumed. When the battery 2106 is depleted, it no longer powers the device 2100 and no longer needs to be replaced, the user can unscrew, unscrew, or twist the outer cover 2114 relative to the rest of the device 2100 . to remove the outer cover 2114 from the rest of the device 2100 . The old battery 2106 in the device 100 can then be removed and a new battery 2106 installed in place. The user can then reinstall the outer cover 2114 over the rest of the device 2100 and resume using the device 2100 .

In some embodiments, the surface of the outer cover 2114 or the remainder of the device 2100 that engages the outer cover 2114 includes detents, the detents locating the outer cover 2114 and the outer cover 2114 on the device 2100 . Engaged when turned against the rest of the device 2100 just prior to being released from the rest. Detent engagement can serve as a signal to the user that outer cover 2114 is about to be released from the rest of device 2100 . When the user removes the outer cover 2114 to release it from the rest of the device 2100, the battery is disconnected and the device is rendered inoperable. Thus, the outer cover 2114 can act as a switch, where removing the outer cover 2114 from the rest of the device 2100 switches off the device 2100 and engages the outer cover 2114 with the rest of the device 2100 . switches the device 2100 to the ON state.

Alternatively or additionally, the dispenser may use a structure (eg, substrate) with one or more nozzles, the nozzles having orifices in the micron size range (eg, 1 micron to 30 microns). . Such nozzles may take advantage of the Raleigh effect, passing through orifices in the micron size range to create jets or streams of fluid that break up into a monodisperse spray of droplets. The desired droplet size can be achieved by properly sizing the orifice, the droplet generally being twice the size of the orifice. Thus, an orifice size in the range of 3.5 microns to 7.5 microns can achieve a median droplet size in the range of 7 microns to 15 microns, while an orifice of 4.5 microns or 5.0 microns A micron orifice can achieve a median droplet size of 9 microns or 10 microns, respectively. The use of nozzles with micron-sized orifices can advantageously reduce variation between droplet sizes in an aerosol, increasing the amount (e.g., mass) of active agent (e.g., salt) delivered to a subject per unit time. may result in more uniformity and/or predictability of Multiple micron-sized orifices can advantageously increase the number of droplets in the aerosol per unit time. Nozzles with micron-sized orifices can be obtained from Medspray of The Netherlands. The nozzle is implemented as part of a mister with a reservoir and associated pump. Manual actuation of the pump can drive fluid from the reservoir through a micron-sized orifice.

Delivery of aerosols, particularly aerosols with fairly consistent droplet sizes, can be advantageous over other forms of delivery such as vapor. Vapors tend to stay longer, tend to stick to surfaces, and are generally more difficult to deliver in precise amounts compared to aerosols. The droplets are also typically able to hold more mass (e.g., more mass of calcium chloride and/or magnesium chloride) in the vapor and deliver an effective amount in less time than via vapor. allow delivery. For example, exposure of droplets having a median size in the range of 7 microns to 15 microns to an aerosol for less than 1 minute (e.g., 10 seconds) is followed by exposure to a vapor of less than 7 microns for several minutes (e.g., 6 minutes). can deliver as much salt as As described herein, control over droplet size can advantageously target the upper respiratory tract, indicating that delivery of small amounts of salt is efficacious compared to delivery not restricted to the upper respiratory tract. enable A targeted droplet size in the range of 7 microns to 15 microns may advantageously facilitate or enhance reverse nasal delivery, which may be more efficient than forward nasal delivery.

Experimental Relevance It was recently observed that nasal saline delivery consisting of a mist of 10 μm droplets containing a mixture of calcium and sodium chloride salts can reduce respiratory droplets by 99% up to 6 hours after administration. Ta. The salt (a hypertonic mixture called Composition A) associates with mucin macromolecules near the mucus surface, binding mucus molecules together, thereby increasing mucus surface tension and surface viscoelasticity. These effects help the mucus surface withstand the stresses that air passes through it during normal breathing, resulting in fewer respiratory droplets in the airways and fewer aerosol particles in exhaled air. This is a form of "airway hygiene."

Airway hygiene follows the millennia-old tradition of nasal saline administration to cleanse the mucus surface of foreign particles. Salts ranging from pure sodium chloride (table salt) at physiological tonicity (0.9% by weight) to more complex mixtures of salts containing calcium chloride, magnesium chloride, etc. have long been used by oral gavage and It has been administered as a nasal spray. Hypertonic salt compositions can particularly increase ciliary beating, facilitating clearance of mucus and associated particulate matter towards the mouth.

The impact of airway hygiene was investigated in US learning facilities (Grand Rapids Michigan and Cape Cod Massachusetts) and compared with a relatively high airborne particle load setting (Bangalore India). Two types of intranasal saline administration (Composition A and plain saline spray) were studied. The findings are reported below.

Method
Human volunteer studies were conducted at Bangalore Baptist Hospital (BBH), Grand Rapids Community College (GRCC), and Cape Cod Academy (CCA). IRB approval was received from the BBH Ethics Committee, GRCC Ethics Committee for these (non-drug-cosmetics) studies, and a waiver of the need for IRB approval of an independent, accredited E&I Review was made for the CCA study. . 440 volunteers were recruited in Bangalore (ages 26-63); 120 volunteers in Grand Rapids (ages 11-68); and 93 volunteers in Cape Cod (ages 10-70). A total of 126 females, 104 males, and 23 uninformed individuals were recruited. Of the 253 human subjects, 82 were Caucasian, 15 African American, 33 Asian, 33 Latino, 49 Indian, and 41 unclaimed. Participants were not screened for SARS CoV-2 infection by serology or polymerase chain reaction (PCR) prior to enrollment. Although none of the subjects were known to be COVID-19 positive, two of the Grand Rapid subjects, a brother (age 16) and a sister (age 19), lived in the same household and were exposed to exhaled aerosols. Asymptomatic carriers were suspected because of abnormally high numbers and sibship. All participants in all studies provided written informed consent prior to enrollment. Figure 8 shows the general design of the protocol for the three laboratories (particularly the GRCC research facility).

Before and after intranasal saline administration, exhaled breath particles were measured by a particle detector (Climet 450-t) designed to count airborne particles in the size range of 0.3-5 micrometers. The particle detector was connected to a standard nebulizer tube and mouthpiece that filtered the incoming air through a HEPA filter. Prior to the subject's first exhaled particle detection, each standard nebulizer tube and mouthpiece was removed from the sealed packaging in front of each subject. In subsequent counting runs, the same mouthpiece, tubing and HEPA filter were replaced by the participant into the particle counter system to ensure effective hygiene. Subjects took one normal breath through the mouthpiece while covering their nose for 1-2 minutes, beginning with two deep breaths to empty their lungs of environmental particles. Over this time frame, the number of particles per liter decreased to a lower baseline number reflecting particles released from disruption of the airway lining fluid surface within the subject's airways. Upon reaching a lower particle count plateau, the subject continued to breathe normally. Three to eight particle counts (average particle counts evaluated over 6 seconds) were then averaged to determine the mean exhaled particle count and standard deviation. Participants sat opposite the study administrator across a Plexiglas® barrier.

Two types of saline were used in the test. Composition A is a drug-free nasal saline hygiene formulation consisting of calcium chloride and sodium chloride in distilled water. The total salinity composition (4× isotonic composition) is in the range of seawater composition, specifically 0.43M CaCl ₂ , 0.05M NaCl (4.72% CaCl ₂ , 0.31% NaCl). Composition A Compositions were manufactured at Pharmasol (MA) in a GMP mixing and filling facility and contained in sealed plastic bottles (0.5 oz). The Composition A bottle was opened and emptied into a glass vial in the Mister apparatus. The handheld vibrating mesh nebulizer was manufactured by Perfect Electronics, Shenzhen, China, with a pore size of 6 μm, and an aerosol with an optimal particle size distribution for delivery to the nose through natural nasal inhalation on the chip of the device. Generate clouds. Produces a median volume particle diameter of 9-10 μm (16), optimal for aerosol deposition in the nose and upper respiratory tract following deep natural tidal inhalation through the nose, with deposition from the front to the back of the nose. With a relatively even distribution of , the Nimbus tipped 57 mg +/- 2 mg within 10 seconds of actuation, after which power was turned off until tipped upright again. The device delivered a dose of approximately 33 mg (1.56 mg CalCl ₂ ) by filling an empty 6 ounce glass with the cloud for a 10 second actuation of the internally programmed device, and then the cloud was filled. Inhale directly into the nose through the glass. Administration can also be accomplished by creating a cloud in front of the nose with a deep nasal breath.

Plain saline by Arm & Hammer, a commercially available saline nasal spray, was purchased and used as a control (one spray per nostril).

Results Total exhaled aerosol vs. ambient inhaled particle mass exposure. The exhaled aerosol particle count and size at the sites were evaluated. At each site, a small group of subjects exhaled approximately 80% of the total group aerosol, following the classic 20:80 rule of "superspread" of infectious disease.

A "superspreader" (of aerosol particles) is considered an individual who exhales 80% of all aerosol particles in a group (albeit less than 20% of all subjects). Classical super-spreader distributions can be found at each US site, with 79.5% of 120 subjects producing group exhaled aerosols at Grand Rapids 24 (20%), and at Cape Cod site , 19 out of 93 (20%) produce 79.7% of group exhaled aerosols. However, only 10% of the Indian subjects (4 of 40) produced 82.6% of the group's exhaled aerosol, while 20% of all subjects (8) produced 95.1 of the total exhaled aerosol. %.

The skewed importance of high emitters in India reflects the fact that exhaled aerosol counts are dramatically higher in India compared to US sites. The top 20% aerosol emitters in Bangalore had a mean exhaled aerosol particle count of 30,585+/-11,380. Mean exhaled aerosols were statistically lower (p < 0.0002) at US sites, specifically 532 +/- 668 at Grand Rapid and 818 +/- 722 at Cape Cod. These differences reflect differences in suspended particulate matter burden between Indian and US sites. The reported particle mass below 10 μm (PM10) over this same time frame in India (Bangalore) was 150 μg/m3, whereas it was an order of magnitude lower for the US site (17 μg/m at Grand Rapid). m3, 7 μg/m3 on Cape Cod).

No statistically significant between-site differences between exhaled aerosols were observed among Caucasian, African American, Asian, Hispanic, or Indian subjects, and no significant differences were observed among subjects of different age or BMI. not observed. Although there was a correlation between exhaled aerosols and years of BMI (BMI multiplied by age), differences in years of BMI among the three study sites were not significant.

Exhaled Aerosol Versus Time After Airway Hygiene Administration The effect of airway hygiene on exhaled aerosol was evaluated as a function of time after administration and compared to a saline nasal spray control in Bangalore.

For subjects administered Composition A (n=20), exhaled aerosol counts decreased within 15 minutes after administration and remained suppressed for at least 3-4 hours (FIG. 10A). For subjects who received saline nasal spray controls (n=20), post-dose exhaled aerosol counts were low and mixed for several hours post-dose (FIG. 10B).

Figures 10C and 10D show the inhibitory effect following Composition A versus nasal saline controls on total exhaled aerosol in all 40 subjects at 2 hours post-dose. The large difference in total exhaled aerosol versus baseline (86%) was highly significant (p<0.011) for Composition A airway hygiene (n=20), while the decrease in total exhaled aerosol (34%) was not significant (p<0.62) for plain saline controls (n=20).

Exhaled Aerosol Suppression by Airway Hygiene Management In Bangalore, Grand Rapids and Cape Cod, the efficacy of nasal saline airway hygiene was evaluated from all subjects before and 15-30 minutes after administration of composition A or plain saline. was evaluated by assessing the exhaled aerosol of Results for the 20% highest emission aerosol subject are shown in Figures 11A-C (Composition A).

Composition A administration resulted in the most significant reduction in exhaled aerosol in the airways of those exhaling the highest number of aerosol particles at each site, with the most significant % reduction being the most significantly elevated in the dirtiest air environments, especially exhaled aerosol. appear in Bangalore. The non-significant individual subject Composition A suppression compared to baseline seen in FIG. 11A vs. FIG. ).

Figures 12A, 12B and 12C show the extent of overall suppression of exhaled aerosol at each site 15-20 minutes after administration for both Composition A and plain saline. Although overall airway cleaning with Simply Saline controls was not significant in all cases (BBH p<0.94, GRCC p<0.83, CCA p<0.65), the overall airway cleaning effect of Composition A was marginally significant at each site tested (BBH p<0.169, GRCC p<0.124, CCA p<0.098), reflecting the large variance in exhaled aerosol counts between Low and Super Spreaders. (FIGS. 11A-C).

Discussion Breath aerosol studies in India and the United States show that prolonged inhalation of high levels of micron and submicron particulate matter can promote the production of large numbers of respiratory droplets, distorting these droplets to submicron size. suggest (Fig. 9). These findings are consistent with the hypothesis that the landing of inhaled particles on the mucus surface reduces surface tension and surface viscoelasticity, facilitating the breakup of airway mucosa into smaller sized droplets.

These trends were observed elsewhere in exhaled aerosols after viral (COVID-19) and bacterial (tuberculosis) infection in non-human primates. Exhaled aerosol increases and exhaled aerosol particle size decreases in conjunction with the growth of viral and bacterial load in lung tissue.

Whether the accumulation of viral and bacterial particles at or near mucus surfaces in the development of respiratory diseases such as COVID-19 and tuberculosis has similar surface property-altering effects as the accumulation of fine particles respired from the atmosphere. Regardless, the findings of this study suggest that respiratory droplet abundance plays a role in the spread of airborne diseases in unclean air environments. This may also explain the observed trend of increased COVID-19 mortality risk in contaminated environments.

Airway hygiene is a simple hygienic intervention that can enable people to meet the respiratory droplet carrier challenge wherever they live. Administration of calcium-enriched nasal saline inhibits droplet break-up by increasing surface viscoelasticity through calcium-mucin interactions, making the upper airways of respiratory droplets the most fouled for several hours. 99% cleansing in the open airways (Fig. 9C). While the effectiveness of airway hygiene can clearly be influenced by the successful application (i.e., deep nasal inspiration) technique, it was significantly manifested within 15 minutes of administration (Fig. 12) and There is remarkable agreement across the parts of It is especially effective for people who breathe dirty air (Figs. 10A, 10C).

By comparison, the nasal saline spray control had little to moderate effect, and no overall effect was observed in the short-term (15-30 min) time frame of FIGS. It was a measure of the effect of 10B over time. This conclusion is consistent with the belief that isotonic saline inhalation suppresses exhaled aerosols and suggests that post-nasal drainage of saline from the nose can reach the trachea in some subjects. can suggest.

Children and young adults (under the age of 26) have been found to exhale very few particles. Of the 120 children and young adults evaluated, only 6 of these young subjects had exhaled breath of 150 particles/L or greater, while 89% of young subjects had between 1 and 50 particles/L. was exhaling air. Of these six, all of these exceptions evoked aerosols in excess of 1000 particles per liter. In three of these cases, subjects 5, 8 and 39 from our Bangalore study, young subjects breathed highly contaminated air into their respiratory tract. In two of the cases, sibs aged 16 and 19 from Grand Rapids, the child was suspected to be an asymptomatic carrier of COVID-19, while one, a 17-year-old male from Cape Cod, had an obvious No causal relationship of airway particle load was observed. Although young people as a rule have few respiratory droplets, they can be high producers of respiratory aerosols, especially their respiratory tracts, whether they are particulate matter present or proliferate, as in infections. Even a virus should be covered by a foreign body.

A combination of environmental and biological factors makes some people significantly more susceptible than others to respiratory illnesses and more susceptible than others to communication of airborne diseases, including COVID-19. Although higher, the results suggest that inhaled particles themselves may be the source of excessive respiratory droplet production and risk of infection and transmission by weakening the airway lining fluid. .
313±145 before 15±27 after

These results show that prior to administration of Composition B, individuals exhaled 313±145 particles per liter, and 30 minutes after administration of Composition B, humans exhaled 15±27 particles per liter. It shows that the effectiveness of composition B has been demonstrated.

Details of the Bangalore Study A randomized, controlled, two-arm trial was conducted in Bangalore, India, to assess whether upper respiratory tract salt hydration reduces symptoms of the delta variant of COVID-19.

Salts delivered to the upper airways increase upper airway hydration and reduce respiratory droplet development. Such a salt-mediated reduction in respiratory droplet production slows the progression of pathogens such as SARS-CoV-2 to the lower respiratory tract and reduces symptoms in mildly symptomatic COVID-19 patients, regardless of the nature of the pathogen. It was hypothesized that it might be mitigated.

METHODS: In a randomized, single-blind, nasal saline-controlled trial at the Bangalore Baptist Hospital, daily administration of calcium-rich hypertonic salts to the upper respiratory tract was associated with delta (6) as a major cause of Bangalore infection. B.1.617.2) Effects on breath aerosols and COVID-19 symptoms over the period in which coronavirus variants emerged (December 2020 to June 2021). The study recruited 84 human subject volunteers among mildly symptomatic COVID-19 patients. Participants were screened for SARS CoV-2 infection by polymerase chain reaction (PCR) prior to enrollment. IRB approval for this study was obtained from the Ethics Committee of Bangalore Baptist Hospital. All participants provided written informed consent prior to enrollment. In this study, symptoms immediately after enrollment were assessed by blood analysis (C-Reactive Protein, d-dimer), lung X-ray, oxygen saturation, body temperature and self-reported symptoms (fever, cough, diarrhea, loss of taste/smell, respiratory difficulty, body pain). Exhaled particles from all participants were measured by a particle detector (Climet 450-t) designed to count airborne particles ranging in size from 0.3 μm to 5 μm or greater. Of the participating COVID-19-positive patients, all participated in exhaled aerosol measurements, but 39 were randomly assigned to two multi-day treatment cohorts. An active (FEND) cohort of 20 subjects was dosed with calcium via a handheld vibrating mesh nebulizer with a median volume droplet diameter of 9-10 μm designed to target the nose, trachea and main bronchi. An enriched hypertonic saline solution (0.43 M CaCl ₂ , 0.05 M NaCl) (4.72% CaCl ₂ , 0.31% NaCl) was nasally inhaled. A (Simply Saline) control cohort of 19 subjects administered by nasal spray of saline (0.9% sodium chloride) three times daily for the first three days after admission to the study. Patients received active and control drugs three times daily for the first three days after admission to the study and were blinded to active and control drugs. Exhaled aerosol was assessed for all active and control patients before and after salt administration, and exhaled aerosol was monitored for 2 hours after delivery. All patients were monitored daily for oxygen levels, temperature, intravenous antibiotics and steroid treatment (if necessary), and self-reported symptoms on a scale of 1-5 (ascending scale from asymptomatic to most severe symptoms). Patients with severity of symptoms that required escalation to intensive care during the first 3 days of hospitalization were excluded from the study. Statistical significance of variable differences was calculated using a multiple-way analysis of variance (ANOVA) test and Student's t-test.

Findings As the delta variant of the SARS-CoV-2 virus spreads in Bangalore, India and becomes the sequenced dominant strain, the study estimates that in the period December 2020-February 2021, 1468+/liter of air per liter of air. From -1883 particles to 8234+/4315 particles per liter of air in early June 2021, we measured an increase in mean breath droplet count among 83 COVID-19 positive patients. In a randomized, controlled, two-arm study at the Bangalore Baptist Hospital, administration of hypertonic calcium and sodium salts (FEND) to the upper respiratory tract of 39 patients resulted in respiratory droplet development of 42.72% +/- 30.51% (P= 0.014), but no decrease was observed 60 minutes after baseline measurement in patients receiving the Simply Saline control (P=0.39). 93% of the Simply Saline group and 55% of the FEND group required daily intravenous antibiotics or steroid intervention for 3 days in participants presenting with severe inflammation (CRP values >10 mg/L) Met. Oxygen saturation was significantly increased in the FEND group (P=1.86e-8), whereas no significant increase in oxygen saturation level was observed in the plain saline group (P=0.128). Self-reported symptom scores were reduced by 55.44%±7.43% in the FEND group, whereas self-reported symptom scores were reduced by 32.18%±7.91% in patients receiving nasal saline spray control. 61% of patients were discharged asymptomatic in the FEND group, whereas 0% were discharged asymptomatic in the nasal saline group.

Interpretation Daily delivery of calcium-rich salts to the upper respiratory tract reduced the need for anti-inflammatory steroid and antibiotic therapy, increased oxygen saturation, and caused mild symptoms in predominantly delta mutant infections. Reduced symptoms of COVID-19 in sexual patients compared to isotonic saline controls. The results suggest that daily administration of a non-drug saline solution to the upper respiratory tract may be a useful hygiene measure to reduce the severity of COVID-19 symptoms regardless of the nature of the COVID-19 variant.

Preface The challenges of rapid mutation and access to vaccination are prolonging the COVID-19 pandemic in low-income regions of the world and threatening human populations. Non-pathogen-specific hygiene approaches for airborne respiratory diseases, equivalent to hand hygiene for gastrointestinal infections, have the potential to save lives in the current global pandemic and reduce respiratory improve organ health.

Upper airway hydration is mediated through a variety of mechanisms, including increased cilia beating frequency and decreased upper airway production of respiratory droplets, which has been shown to be a major vector for SARS-CoV-2 transmission. and appear to reduce the risk of airborne infections. Nasal administration of a hypertonic mist of divalent calcium and magnesium salts with a median diameter droplet size of 9-10 μm was associated with 4-6 Over time, it is believed to be a particularly effective means of upper airway hydration to reduce respiratory droplet production. Inhalation of a mist of 9-10 μm droplets targets hypertonic salts to the trachea and main bronchi, where the major hydration of incoming air occurs, and a non-drug hydration approach clears the airways of respiratory droplets. , irrespective of pathogen type, can potentially reduce the movement of inhaled pathogens (and other contaminants) deposited in the upper respiratory tract to the deep lung, where they can promote severe symptoms.

Applicants have found that in human subjects infected with COVID-19, intranasal administration of a calcium-rich hypertonic saline solution three times daily into the upper respiratory tract has been shown to significantly reduce symptoms in recently infected, mildly symptomatic subjects. Potentially symptomatic and effective non-infective against highly contagious variants of SARS-CoV-2, including the δ variant (B.1.617.2), which first appeared in India in October 2020. A drug strategy was hypothesized. To explore this hypothesis, in the present study, from December 2020 to June 2021, in Bangalore Baptist hospital, hospitalized COVID -19 positive patients were mobilized. In this study, exhaled aerosol was assessed in all volunteers and a subset of volunteers were included in a randomized controlled two-arm study as reported in this paper.

METHODS Study design and participants This study included volunteers aged 16-57 years among COVID-19 patients with mild symptoms at Bangalore Baptist Hospital (BBH) during the pandemic period (December-June 2021) in India. 84 cases were recruited. During this period, delta (B.1.617.2) coronavirus variant BBH infections were sequenced, increasing from a few cases to 70% of infections in India (14). Participants were screened for SARS CoV-2 infection by polymerase chain reaction (PCR) prior to enrollment. IRB approval for this study was obtained from the Ethics Committee of Bangalore Baptist Hospital. All participants provided written informed consent prior to enrollment. Symptoms of all 84 participants were assessed by blood markers of inflammation (CRP, d-dimer), lung x-ray, pulse oximetry, body temperature and self-reported symptoms (fever, cough, diarrhea, loss of taste/smell, dyspnea, body pain). pain) was assessed immediately after enrollment by analysis. Exhaled particles from all participants were measured by a particle detector (Climet 450-t) designed to count airborne particles ranging in size from 0.3 μm to 5 μm or greater. Thirty-nine participants were randomly assigned to two treatment cohorts. An active (FEND) cohort of 20 subjects was dosed with calcium via a handheld vibrating mesh nebulizer with a median volume droplet diameter of 9-10 μm designed to target the nose, trachea and main bronchi. An enriched hypertonic saline solution (0.43 M CaCl ₂ , 0.05 M NaCl) (4.72% CaCl ₂ , 0.31% NaCl) was nasally inhaled. An A (saline only) control cohort of 19 subjects was administered saline (0.9% sodium chloride) by intranasal spray. All participants received active or control three times daily for the first three days after study initiation. Patients were blinded to receiving active or control. In this study, we assessed all activity and exhaled aerosols in control patients before and after salt administration and monitored exhaled aerosols 1-2 hours after delivery. All patients will be monitored daily for oxygen saturation, temperature, intravenous antibiotics and steroid therapy (if necessary), and self-reported symptoms on a scale of 1-5 (ascending from no symptoms to most severe symptoms). did. Patients who required supplemental oxygen before admission or during the first 3 days after admission (blood oxygen saturation <95%) were excluded from the study.

Procedure Breath particles were measured before and after administration of active or control by a particle detector (Climet 450-t) designed to count airborne particles in the size range from 0.3 μm to over 5 μm. The particle detector air port was attached by flexible plastic tubing to the side of the 1″ inner diameter tubing (by a T-connector) through which the subject inhaled and exhaled, the 1″ tubing being a mouse with a standard nebulizer tube at one end. The pieces were connected and a portable HEPA filter was connected to the other end. The entire tubing system tightly sealed the subject's lips around the mouthpiece and facilitated the filtration of all environmental particles from the subject's lungs for approximately 1 minute of nose pinch breathing. The particle counter flow rate (50 L/min) was near the typical peak inspiratory/expiratory flow rates of human subject respiration so that the direction of airflow remains in the particle counter. Prior to the subject's first exhaled particle detection, each standard nebulizer tube and mouthpiece was removed from the sealed packaging in front of each subject. At subsequent counting runs, the same mouthpiece, tubing and HEPA filter were reattached by the participant to ensure the absence of contamination from one subject to the next. Prior to each test, the mouthpiece was replaced with a stopper and the particle detector was turned on to ensure that no particles escaped from the environment. Less than 10 particles per liter of air were considered "sealed" and when the mouthpiece was put back into the tube, the subject was allowed to breathe normally through the mouthpiece for 1-2 minutes while covering the nose with a finger. Take a tidal breath, starting with two deep breaths to empty your lungs of environmental particles. Over this time frame, the particle counts per liter of air drawn into the particle counter from exhaled air decreased and subsequently fluctuated around baseline numbers. Considering the external environment, tight lip seals and ensuring no leaks from pinched noses, we equate this baseline number to the particles generated in the subject's airways. assumed. Subjects who reached a lower particle count plateau continued to breathe normally for determination of exhaled aerosol particle counts. Participants sat opposite the study administrator across a Plexiglas® barrier. The Climet 450-t particle counter reports particle counts as a function of aerodynamic particle size range for particles >0.3 μm, >0.5 μm, >1 μm, and all >5 μm are doing. The reported numbers represent the average number of particles automatically measured by the light scattering detector over 6 seconds. For determination of exhaled aerosol particle counts, the study averaged 3-8 average particle counts (6 s each) as reported by the particle detector to determine the average exhaled particle count and standard deviation. Integrate the interval) was performed.

Blood samples were taken and tests (ie C-reactive protein (CRP), D-dimer) were performed to detect Covid-19. Oxygen saturation levels were measured by pulse oximetry. Patients with high levels of inflammation and concomitant symptoms received intravenous antibiotics or intravenous steroids. Patients were dosed to intensive care and removed from the study if their oxygen levels fell below prescribed levels.

Results The primary outcomes were exhaled aerosol particle count, need for intravenous antibiotics or anti-inflammatory steroids, and oxygen saturation. Secondary outcomes were daily self-reported symptom scores. Data from this study are presented in Figures 13A, 13B, 13C, 13D, 14A, 14B, 14C, 15A, 15B, 16A, 16B, and 16C.

Statistical Analysis All error bars represent 95% confidence intervals based on standard deviation values. The significance of differences in individual and collective aerosol counts was determined by the twin-tailed T-test. Statistical significance of differences was calculated using a multiple-way analysis of variance (ANOVA) test for each variable set. This allowed us to assess the influence of multiple factors on the mean within 95% confidence intervals. P-values were calculated for each unique set of variables compared to baseline values. Each P-value less than 0.05 was considered statistically different.

FIG. 13A shows a bar graph of exhaled particle counts from a study of a set of human subjects who exhibited mild COVID-19 symptoms prior to treatment, according to at least one exemplary implementation. In particular, exhaled breath particles were produced prior to application of the calcium chloride aerosol in droplets having a median droplet size of about 10 microns for one cohort and a median droplet size of about 10 microns for another cohort. was collected prior to application of sodium chloride (saline) aerosol in droplets with

FIG. 13B shows as a bar graph the baseline value of mean exhaled particle count for human subjects in the study as a function of infection duration, according to at least one exemplary implementation. Error bars represent standard error of the mean.

FIG. 13C shows as a scatter plot of baseline values for mean exhaled particle counts for human subjects as a function of age, according to at least one exemplary implementation.

FIG. 13D shows a scatter plot of human subjects' C-reactive protein levels as a function of age, according to at least one illustrated implementation.

FIG. 14A shows corresponding baseline versus time following baseline measurements for a subset of human subjects following administration of hypertonic calcium-rich salts targeting the upper respiratory tract of the respiratory tract (FEND), according to at least one exemplified implementation. Shown as a line graph of the percentage (%) change in mean exhaled particle count from measurement.

FIG. 14B shows the mean from corresponding baseline measurements versus time following baseline measurements for a subset of human subjects after administration of a nasal saline spray (just saline), according to at least one exemplified implementation. The percentage (%) change in exhaled particle count is shown as a line graph.

FIG. 14C shows the percentage change in mean exhaled particle count from the corresponding baseline measurement versus time following the baseline measurement for a subset of human subjects, including an untreated control group, in accordance with at least one exemplified implementation (% ) as a line graph of change. The untreated group was not treated with hypertonic calcium-rich salts targeting the upper respiratory tract (FEND) and was not treated with nasal saline spray (just saline).

FIG. 15A depicts a first cohort administered hypertonic calcium salt (FEND) targeting the upper respiratory tract and a second cohort administered plain saline for hyperinflammation according to at least one exemplary implementation. 10 shows as a bar graph the proportion (%) of study subjects who had required intravenous antibiotic or steroid intervention. The first cohort receiving hypertonic calcium salts targeting the upper respiratory tract (FEND) included 9 of 20 subjects. A second cohort receiving saline contained 9 of 19 cases.

Figure 15B shows, respectively, i) a population that received a calcium chloride sanitary and/or antimicrobial formulation or composition; ii) a population that received a sodium chloride (saline) sanitary and/or antimicrobial formulation or composition; iii) Shown as a bar graph of oxygen saturation percentages over days 1, 2, and 3 for a human control population that was not administered a salt-based sanitary and/or antimicrobial formulation or composition. Error bars represent standard error of the mean.

FIG. 16A shows as a bar graph self-reported symptom scores as a function of days of hospitalization and dosing over the first three days of FEND, according to at least one exemplified implementation. Self-reported symptom scores are reported on a scale of 1 to 5, with 1=no symptoms and 5=most severe symptoms.

FIG. 16B shows as a bar graph self-reported symptom scores as a function of days of hospitalization and administration over the first three days of plain saline as a control, according to at least one exemplified implementation. Self-reported symptom scores are reported on a scale of 1 to 5, with 1=no symptoms and 5=most severe symptoms.

FIG. 16C shows as a bar graph self-reported symptom score as a function of hospital days without administration of nasal salts, according to at least one illustrated embodiment. Self-reported symptom scores are reported on a scale of 1 to 5, with 1=no symptoms and 5=most severe symptoms.

Examples Example 1:
An aerosol composition of droplets comprising a salt-based composition, each droplet comprising:
from about 1% to about 10% by weight of calcium chloride and/or magnesium chloride in water;
The composition, wherein said droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns.
Example 2:
A composition according to example 1, wherein said droplets comprise more than 1% by weight of calcium chloride and/or magnesium chloride.
Example 3:
The composition of Example 1, wherein the salt-based composition is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride.
Example 4:
The salt-based composition comprises an essential oil, aromatic oil or essential oil, cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil, palm oil, fig oil, grapefruit oil, hazelnut oil, honey melon oil, lavender or spike lavender. oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise extract, rose oil, linalool-containing oil, and combinations thereof, further comprising a flavor extract.
Example 5:
The composition of any of Examples 1-3, wherein said salt-based composition comprises calcium chloride and/or magnesium chloride and at least 10% by weight of ethyl alcohol.
Example 6:
The composition of any of Examples 1-3, wherein the droplets comprise from about 4% to about 10% by weight calcium chloride and/or magnesium chloride.
Example 7:
The composition of any of Examples 1-3, wherein the droplets comprise from about 1% to about 5% by weight calcium chloride and/or magnesium chloride.
Example 8:
The composition of any of Examples 1-3, wherein the droplets have a mass median droplet diameter ranging from 9 microns to 10 microns.
Example 9:
The composition of any of Examples 1-3, wherein the droplets have a mass median droplet diameter of about 9.5 microns with a standard deviation of less than 1 micron.
Example 10:
The composition of any of Examples 1-3, wherein the droplets have a mass median droplet diameter ranging from 7 microns to 15 microns with a standard deviation of less than 5 microns.
Example 11:
The composition of any of Examples 1-3, wherein a majority of said droplets have a droplet size between 9 and 10 microns in diameter.
Example 12:
The composition of Example 11, wherein a majority of said droplets have a droplet size of about 9.5 microns in diameter.
Example 13:
The composition of any of Examples 1-3, wherein said salt-based composition comprises a preservative selected from the group consisting of benzalkonium chloride, benzoic acid, and benzoyl alcohol.
Example 14:
The composition of Example 13, wherein said preservative is benzalkonium chloride.
Example 15:
The composition of Example 14, wherein said benzalkonium chloride is present in an amount ranging from about 0.05% to about 0.2% by weight.
Example 16:
The composition of any of Examples 1-3, wherein the salt-based composition comprises an amount of acid sufficient to lower the pH of the salt-based composition from about 2 to about 6.
Example 17:
The composition of Example 16, wherein said pH ranges from about 2 to about 3.
Example 18:
The composition of Example 15, wherein said acid is citric acid, hydrochloric acid, or a combination thereof.
Example 19:
Example 1 or 2, wherein the salt-based composition comprises from about 1.0% to about 6.0% by weight calcium chloride and from about 0.1% to about 1.5% by weight sodium chloride. The described composition.
Example 20:
20. The salt-based composition of Example 19, wherein the salt-based composition comprises from about 1.0% to about 2.0% by weight calcium chloride and from about 0.5% to about 1.5% by weight sodium chloride. Composition.
Example 21:
The composition of Example 19, wherein said salt-based composition comprises about 4.0-6.0% by weight calcium chloride and about 0.1% to about 0.5% by weight sodium chloride.
Example 22:
(a) a dry powder containing calcium chloride and/or magnesium chloride; and (b) a sterile solution of a water-based composition comprising:
(1) a preservative selected from the group consisting of benzalkonium chloride, benzoic acid and benzoyl alcohol; or (2) an acid in an amount sufficient to lower the pH of the salt-based composition from about 2 to about 6. and wherein said dry powder can be mixed with said water-based composition to form a salt-based composition.
Example 23:
23. The composition of example 22, wherein said water-based composition comprises said preservative selected from the group consisting of benzalkonium chloride, benzoic acid and benzoyl alcohol.
Example 24:
The composition of Example 23, wherein said preservative is benzalkonium chloride.
Example 25:
The composition of Example 22, wherein said water-based composition comprises an amount of said acid sufficient to lower the pH of said salt-based composition to about 2 to about 4.
Example 26:
The composition of Example 22, wherein the pH of said salt-based composition ranges from about 2 to about 6.
Example 27:
The composition of Example 26, wherein said pH ranges from about 2 to about 5.
Example 28:
The composition of Example 25, wherein said acid is citric acid, hydrochloric acid, or a combination thereof.
Example 29:
The composition of Example 22, wherein the dry powder is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride.
Example 30:
The composition of example 22, wherein the dry powder is in a sachet.
Example 31:
A method of administering a formulation or composition to the nasal, tracheal and major bronchi of a subject's respiratory tract to inhibit viral shedding, comprising:
generating an aerosol of droplets in a space, said aerosol being naturally inhalable by said subject without exerting any force on said nose, trachea and main bronchi of said airways of said subject; including said step;
said droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water;
The method, wherein the droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns.
Example 32:
32. The method of example 31, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets comprise more than 1% by weight of calcium chloride and/or magnesium chloride.
Example 33:
Example 31, wherein generating the aerosol of droplets comprises generating the aerosol of droplets, wherein the salt-based composition is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride The method described in .
Example 34:
The step of generating an aerosol of droplets is such that the salt-based composition comprises an essential oil, aromatic oil or cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil, palm oil, fig oil, grapefruit oil, hazelnut oil. oil, honey melon oil, lavender or spike lavender oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise. 34. The method of any of Examples 31-33, comprising generating an aerosol of droplets further comprising a flavor extract selected from the group consisting of an extract, rose oil, linalool-containing oil, and combinations thereof. Method.
Example 35:
Examples 31-, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein the salt-based composition comprises calcium chloride and/or magnesium chloride and at least 10% by weight ethyl alcohol 34. The method according to any of 33.
Example 36:
33. The method of example 32, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets comprise more than 4% by weight of calcium chloride and/or magnesium chloride.
Example 37:
Any of Examples 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets have a mass median droplet diameter in the range of 9 microns to 10 microns. The method described in Crab.
Example 38:
Examples 31-, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets have a mass median droplet diameter of about 10 microns with a standard deviation of less than 1 micron 34. The method according to any of 33.
Example 39:
Producing an aerosol of droplets comprises producing an aerosol of droplets, said droplets having a mass median droplet diameter in the range of 7 microns to 15 microns with a standard deviation of less than 1 micron. , the method of any of Examples 31-33.
Example 40:
34. Any of Examples 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein a majority of said droplets have a droplet size between 9 microns and 10 microns in diameter The method described in Crab.
Example 41:
Any of Examples 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein a majority of said droplets have a droplet size of about 9.5 microns in diameter. described method.
Example 42:
The method of any of Examples 31-33, further comprising the subject inhaling an amount of aerosol droplets comprising between 0.5 mg and 4.0 mg of calcium chloride and/or magnesium chloride.
Example 43:
34. The method of any of Examples 31-33, wherein generating an aerosol of droplets comprises providing the aerosol of droplets to a free space into which the aerosol of droplets is inhaled.
Example 44:
44. The method of example 43, further comprising slowing the velocity of the aerosol relative to the velocity as the aerosol leaves the dispenser, from which the aerosol becomes relatively stationary.
Example 45:
34. The method of any of Examples 31-33, further comprising providing said aerosol within a range of 12 inches to 1 inch from said subject's nose.
Example 46:
Any of examples 31-33, further comprising providing the aerosol at a distance sufficiently far from the subject's nose such that the aerosol has at least zero or negligible net velocity horizontally with respect to the earth. described method.
Example 47:
Wherein said step of generating an aerosol of droplets comprises providing the aerosol to an at least partially enclosed space in the form of a container, from which said aerosol is inhalable through an opening in the container. The method of any of Examples 31-33.
Example 48:
said step of generating an aerosol of droplets in response to an activation event generating said aerosol for a predetermined period of time, and after said predetermined period of time until a subsequent activation event; The method of any of Examples 31-33, comprising stopping the
Example 49:
The step of generating an aerosol of droplets includes repeatedly generating the aerosol for a predetermined period of time, during which the aerosol generation ceases to deliver a plurality of doses over a period of time. The method of any of Examples 31-33, separated by time periods.
Example 50:
34. The method of any of Examples 31-33, wherein said generating an aerosol of droplets comprises providing said aerosol in a free space within a venue before and/or during an event.
Example 51:
51. The method of example 50, wherein providing the aerosol in free space within a venue before and/or during an event comprises providing the aerosol in free space at an entrance to the venue.
Example 52:
Providing the aerosol in free space within a venue prior to and/or during an event includes providing the aerosol in free space in a queue for the event through which subjects continuously pass. 51. The method of embodiment 50, wherein the providing step is performed continuously or periodically over an extended period of time over which access to the event is provided.
Example 53:
The step of providing said aerosol in free space in a queue for said event through which subjects pass successively comprises two or more along the length of the queue path used to access said event. 53. The method of example 52, comprising providing said aerosol at said location.
Example 54:
The step of providing said aerosol in free space in a queue for said event through which subjects pass successively comprises: Example 52, comprising providing an aerosol, wherein said predetermined portion is of sufficient length to provide a measured dose to each subject traversing said predetermined portion of said queue path at walking speed. described method.
Example 55:
sequentially reading identifying information from each subject passing through the aerosol;
53. The method of example 52, further comprising: storing information representative of each subject's passage through the aerosol.
Example 56:
continuously identifying information from each subject passing through said aerosol via at least one machine-readable symbol reader, radio frequency identification (RFID) interrogator, or via a facial recognition-based camera and processor-based computer system; a step of reading into
55. The method of example 54, further comprising: storing information representing the amount of time each subject was exposed to said aerosol on at least one non-transitory processor-readable medium.
Example 57:
51. The method of example 50, wherein generating the aerosol of droplets comprises generating the aerosol of droplets wherein the salt-based composition is a purely sanitary composition.
Example 58:
Example 50, wherein generating an aerosol of droplets comprises administering a therapeutically effective amount of said salt-based composition to said subject to generate an aerosol of droplets for inhibiting viral shedding. described method.
Example 59:
wherein the method of administering the formulation or composition to the nose, trachea and main bronchi of the respiratory tract of the subject while the subject is tilting the head back or in a reclining position that promotes post-nasal drip; 32. The method of example 31, comprising administering the salt-based composition to the nose of the subject.
Example 60:
administering the salt-based composition to the nose of the subject administering the salt-based composition to the nose of the subject for 5-10 seconds while the subject's head is tilted 60. The method of example 59, comprising the step of:
Example 61:
administering the salt-based composition to the nose of the subject administering the salt-based composition to the nose of the subject for 30 seconds or more while the subject is in a reclining position; The method of Example 59, comprising
Example 62:
A method of inhibiting exhalation of particles in the upper respiratory tract of a subject, comprising:
generating an aerosol of droplets of a salt-based composition comprising calcium chloride and/or magnesium chloride, said droplets having a mass median droplet diameter ranging from about 7 microns to about 15 microns. , the step;
administering said aerosol of droplets to airway mucosal mucus in said subject's nose, trachea and main bronchi, thereby suppressing said exhalation of particles in said subject's upper respiratory tract.
Example 63:
63. The method of example 62, wherein generating an aerosol of droplets comprises generating an aerosol of droplets comprising calcium chloride and/or magnesium chloride in water.
Example 64:
64. The method of any of examples 62 or 63, wherein administering the aerosol of droplets comprises administering the aerosol of droplets while suspended in a stationary cloud.
Example 65:
A delivery system operable to deliver a purely hygienic or antimicrobial formulation or composition to the nasal, tracheal and major bronchi of a subject's respiratory tract, said delivery system comprising:
a reservoir having at least one wall that at least partially separates an interior of the reservoir from an exterior thereof, the reservoir having a port that provides a fluid communication path between the interior of the reservoir and its exterior; said reservoir, at least in use, holding said hygienic or antimicrobial formulation or composition comprising a quantity of water and at least calcium chloride and/or magnesium chloride dissolved in said water;
at least one delivery device, said at least one delivery device comprising readily soluble droplets having a mass median diameter range of about 7 microns to about 15 microns; A delivery system comprising: said delivery device operable to cause formation of an aerosol comprising calcium.
Example 66:
said at least one delivery device comprising at least one orifice having a size ranging from 3.5 microns to 7.5 microns and at least one pump operable to dispense a jet from said at least one orifice; 66. The delivery system of example 65, comprising:
Example 67:
the at least one delivery device comprising:
at least one nebulizer delivery device, said at least one nebulizer delivery device comprising an actuator, said actuator comprising a readily soluble droplet having a mass median diameter range of about 7 microns to about 15 microns; 66. The delivery system of example 65, comprising said nebulizer delivery device controllably operable on an active agent vehicle to cause formation of an aerosol comprising at least calcium chloride dissolved in said volume of water. .
Example 68:
68. The delivery system of embodiment 67, wherein said at least one nebulizer delivery device is a nebulizer and further comprising a respective control subsystem communicatively coupled to control said actuator.
Example 69:
said at least one nebulizer delivery device comprising a mesh screen mounted for vibration, a microcontroller, and said mesh screen along at least one axis in response to signals from said microcontroller to dispense an aerosol. 68. The delivery system of example 67, which is a nebulizer comprising at least one of a piezoelectric transducer, a solenoid, or an electric motor drivingly coupled to vibrate the .
Example 70:
68. The delivery of embodiment 67, further comprising at least one switch or sensor communicatively connected to the microcontroller and operable by the microcontroller to generate a signal to operate the actuator in response. system.
Example 71:
communicatively connected to the microcontroller and operable to generate a signal to the microcontroller to operate the actuator in response to the at least one nebulizer delivery device being tilted with respect to a normal position or an upright position; 68. The delivery system of example 67, further comprising at least one switch or sensor.
Example 72:
at least one switch or sensor communicatively coupled to the microcontroller and responsive to the position or orientation of a container and operable to generate a signal that causes the microcontroller to operate the actuator in accordance with the orientation of the container; 68. The delivery system of example 67, further comprising:
Example 73:
68. The delivery device of example 67, wherein said at least one nebulizer delivery device is removably dockable to said reservoir.
Example 74:
a measured amount of calcium chloride and/or magnesium chloride;
a container sized to receive a defined amount of water for dissolving the calcium chloride;
A kit for suppressing exhalation of particles in the upper respiratory tract of a subject, comprising instructions.
Example 75:
75. The kit of example 74, wherein said amount of calcium chloride and/or magnesium chloride is self-sealed.
Example 76:
75. The kit of example 74, further comprising, apart from said measured amount of calcium chloride, at least one measured amount of distilled or sterile water sealed in its own sealed package.
Example 77:
A method of administering a formulation or composition to the nose, trachea and main bronchi of a subject's respiratory tract comprising:
generating an aerosol of droplets in a space from which the aerosol can be inhaled by the subject into the nose, trachea and main bronchi of the airways of the subject without the application of force. and
said droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water;
The method of administering the formulation or composition to the nose, trachea and main bronchi of the respiratory tract of the subject while the subject tilts the head back or is in a reclining position that promotes post nasal drip. 2., accomplished by spraying said salt-based composition into said nose of said subject.
Example 78:
A composition of aerosol droplets comprising a salt-based composition,
about 1% to about 5% by weight of calcium chloride and benzalkonium chloride preservatives in water, or
A composition of aerosol droplets comprising a salt-based composition comprising a sufficient amount of acid to lower the pH of said salt-based composition to about 2 to about 3.
Example 79:
The composition of Example 78, wherein said salt-based composition further comprises magnesium chloride.
Example 80:
The composition of any of Examples 78 or 79, wherein the droplets have a mass median droplet diameter ranging from 7 microns to 15 microns.
Example 81:
The composition of example 80, wherein a majority of said droplets have a droplet size between 9 and 10 microns in diameter.
Example 82:
The composition of Example 78, wherein said salt-based composition comprises a benzalkonium chloride preservative, said benzalkonium chloride being present in an amount ranging from about 0.05% to about 0.2% by weight. thing.
Example 83:
79. The composition of Example 78, wherein said salt-based composition comprises said acid, said acid is citric acid, hydrochloric acid, or a combination thereof.
Example 84:
The composition of Example 78, wherein said composition is in the form of a 20 mg to 30 mg dose.
Example 85:
The method of Example 84, wherein a dose of formulation of 20 mg to 30 mg is administered intranasally to said subject.

Applicant incorporates this application by reference. U.S. Provisional Application No. 62/687,970 filed June 21, 2018; U.S. Provisional Application No. 62/628,395 filed April 3, 2018; U.S. Patents filed September 11, 2017 Provisional Application No. 62/556,974, U.S. Provisional Application No. 62/727,123 filed September 5, 2018, U.S. Provisional Application No. 6/122,673 filed September 5, 2018 , U.S. Provisional Patent Application No. 63/048,421, filed July 6, 202 U.S. Provisional Patent Application No. 63/121,448 (filed December 23, 2020), U.S. Patent Application No. 17/139, 401 (filed December) 31, 2020; and International Patent Application PCT/US2018/050250 (published as WO 2019/051403)

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The various embodiments described above can be combined to provide further embodiments. These and other changes can be made to these embodiments in light of the above detailed description. In general, the language used in the following claims should not be construed to limit the scope of the claims to the particular embodiments disclosed in the specification and claims; The claims are to be construed to include all possible embodiments, along with the full scope of equivalents to which they are entitled. Accordingly, the claims are not limited by the disclosure.

Claims (85)

An aerosol composition of droplets comprising a salt-based composition, each droplet comprising:
from about 1% to about 10% by weight of calcium chloride and/or magnesium chloride in water;
The composition, wherein said droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns. 2. The composition of claim 1, wherein said droplets contain more than 1% by weight of calcium chloride and/or magnesium chloride. 2. The composition of claim 1, wherein the salt-based composition is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride. The salt-based composition comprises an essential oil, aromatic oil or essential oil, cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil, palm oil, fig oil, grapefruit oil, hazelnut oil, honey melon oil, lavender or spike lavender. oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise extract, rose oil, linalool-containing oil, and combinations thereof, further comprising a flavor extract. Composition according to any of the preceding claims, wherein the salt-based composition comprises calcium chloride and/or magnesium chloride and at least 10% by weight of ethyl alcohol. A composition according to any preceding claim, wherein said droplets comprise from about 4% to about 10% by weight of calcium chloride and/or magnesium chloride. A composition according to any preceding claim, wherein said droplets comprise from about 1% to about 5% by weight of calcium chloride and/or magnesium chloride. A composition according to any preceding claim, wherein the droplets have a mass median droplet diameter in the range of 9 microns to 10 microns. The composition of any of claims 1-3, wherein the droplets have a mass median droplet diameter of about 9.5 microns with a standard deviation of less than 1 micron. The composition of any of claims 1-3, wherein the droplets have a mass median droplet diameter in the range of 7 microns to 15 microns with a standard deviation of less than 5 microns. A composition according to any preceding claim, wherein a majority of said droplets have a droplet size between 9 microns and 10 microns in diameter. 12. The composition of claim 11, wherein a majority of said droplets have a droplet size of about 9.5 microns in diameter. A composition according to any preceding claim, wherein the salt-based composition comprises a preservative selected from the group consisting of benzalkonium chloride, benzoic acid, and benzoyl alcohol. 14. The composition of claim 13, wherein said preservative is benzalkonium chloride. 15. The composition of claim 14, wherein said benzalkonium chloride is present in an amount ranging from about 0.05% to about 0.2% by weight. 4. The composition of any of claims 1-3, wherein the salt-based composition comprises a sufficient amount of acid to lower the pH of the salt-based composition from about 2 to about 6. 17. The composition of claim 16, wherein said pH ranges from about 2 to about 3. 16. The composition of Claim 15, wherein the acid is citric acid, hydrochloric acid, or a combination thereof. 3. The salt-based composition of claim 1 or 2, wherein the salt-based composition comprises from about 1.0% to about 6.0% by weight calcium chloride and from about 0.1% to about 1.5% by weight sodium chloride. The described composition. 20. The salt-based composition of claim 19, wherein the salt-based composition comprises from about 1.0% to about 2.0% by weight calcium chloride and from about 0.5% to about 1.5% by weight sodium chloride. Composition. 20. The composition of claim 19, wherein the salt-based composition comprises about 4.0-6.0% by weight calcium chloride and about 0.1% to about 0.5% by weight sodium chloride. (a) a dry powder containing calcium chloride and/or magnesium chloride; and (b) a sterile solution of a water-based composition comprising:
(1) a preservative selected from the group consisting of benzalkonium chloride, benzoic acid and benzoyl alcohol; or (2) an acid in an amount sufficient to lower the pH of the salt-based composition from about 2 to about 6. and wherein said dry powder can be mixed with said water-based composition to form a salt-based composition. 23. The composition of Claim 22, wherein said water-based composition comprises said preservative selected from the group consisting of benzalkonium chloride, benzoic acid and benzoyl alcohol. 24. The composition of claim 23, wherein said preservative is benzalkonium chloride. 23. The composition of claim 22, wherein said water-based composition comprises an amount of said acid sufficient to lower the pH of said salt-based composition to about 2 to about 4. 23. The composition of claim 22, wherein the pH of said salt-based composition ranges from about 2 to about 6. 27. The composition of claim 26, wherein said pH ranges from about 2 to about 5. 26. The composition of Claim 25, wherein the acid is citric acid, hydrochloric acid, or a combination thereof. 23. The composition of claim 22, wherein the dry powder is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride. 23. The composition of Claim 22, wherein the dry powder is in a sachet. A method of administering a formulation or composition to the nasal, tracheal and major bronchi of a subject's respiratory tract to inhibit viral shedding, comprising:
generating an aerosol of droplets in a space, said aerosol being naturally inhalable by said subject without exerting any force on said nose, trachea and main bronchi of said airways of said subject; including said step;
said droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water;
The method, wherein the droplets have a mass median droplet diameter ranging from about 7 microns to about 15 microns. 32. The method of claim 31, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein the droplets comprise more than 1% by weight of calcium chloride and/or magnesium chloride. 31. Generating the aerosol of droplets comprises generating the aerosol of droplets wherein the salt-based composition is free of sodium chloride or contains no more than 0.1% by weight of sodium chloride. The method described in . The step of generating an aerosol of droplets is such that the salt-based composition comprises an essential oil, aromatic oil or cocoa oil, caramel oil, cinnamon bark oil, coffee oil, eucalyptus oil, palm oil, fig oil, grapefruit oil, hazelnut oil. oil, honey melon oil, lavender or spike lavender oil, lemongrass oil, lime oil, black or green capsicum oil, peppermint oil, rosemary oil, strawberry oil, smoked oil, tobacco vanilla oil, vanilla oil, chocolate extract, anise. 34. The method of any of claims 31-33, comprising generating an aerosol of droplets further comprising a flavor extract selected from the group consisting of extracts, rose oil, linalool-containing oils, and combinations thereof. Method. 31-, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein the salt-based composition comprises calcium chloride and/or magnesium chloride and at least 10% by weight ethyl alcohol 34. The method according to any of 33. 33. The method of claim 32, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein the droplets comprise more than 4% by weight of calcium chloride and/or magnesium chloride. 34. Any of claims 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets have a mass median droplet diameter in the range of 9 microns to 10 microns. The method described in Crab. 31-, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein said droplets have a mass median droplet diameter of about 10 microns with a standard deviation of less than 1 micron 34. The method according to any of 33. Producing an aerosol of droplets comprises producing an aerosol of droplets, said droplets having a mass median droplet diameter in the range of 7 microns to 15 microns with a standard deviation of less than 1 micron. , the method according to any one of claims 31-33. 34. Any of claims 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein a majority of said droplets have a droplet size between 9 microns and 10 microns in diameter. The method described in Crab. 34. Any of claims 31-33, wherein generating an aerosol of droplets comprises generating an aerosol of droplets, wherein a majority of said droplets have a droplet size of about 9.5 microns in diameter. described method. The method of any of claims 31-33, further comprising the subject inhaling an amount of aerosol droplets comprising between 0.5 mg and 4.0 mg calcium chloride and/or magnesium chloride. 34. The method of any of claims 31-33, wherein generating an aerosol of droplets comprises providing the aerosol of droplets to a free space into which the aerosol of droplets is inhaled. 44. The method of claim 43, further comprising slowing the velocity of the aerosol relative to the velocity as the aerosol leaves the dispenser, from which the aerosol becomes relatively stationary. 34. The method of any of claims 31-33, further comprising providing the aerosol within a range of 12 inches to 1 inch from the subject's nose. 34. Any of claims 31-33, further comprising providing the aerosol at a distance sufficiently far from the subject's nose such that the aerosol has at least zero or negligible net velocity horizontally with respect to the earth. described method. wherein said step of generating an aerosol of droplets comprises providing the aerosol to an at least partially enclosed space in the form of a container, from which said aerosol is inhalable through an opening in the container. Item 34. The method of any one of Items 31-33. said step of generating an aerosol of droplets in response to an activation event generating said aerosol for a predetermined period of time, and after said predetermined period of time until a subsequent activation event; A method according to any of claims 31-33, comprising the step of stopping The step of generating an aerosol of droplets includes repeatedly generating the aerosol for a predetermined period of time, during which the aerosol generation ceases to deliver a plurality of doses over a period of time. A method according to any of claims 31-33, separated by time periods. 34. A method according to any of claims 31-33, wherein said step of generating an aerosol of droplets comprises providing said aerosol in a free space within a venue before and/or during an event. 51. The method of claim 50, wherein providing the aerosol in free space within a venue before and/or during an event comprises providing the aerosol in free space at an entrance to the venue. Providing the aerosol in free space within a venue prior to and/or during an event includes providing the aerosol in free space in a queue for the event through which subjects continuously pass. 51. The method of claim 50, wherein the providing step is performed continuously or periodically over an extended period of time over which access to the event is provided. The step of providing said aerosol in free space in a queue for said event through which subjects pass successively comprises two or more along the length of the queue path used to access said event. 53. The method of claim 52, comprising providing the aerosol at the above location. The step of providing said aerosol in free space in a queue for said event through which subjects pass successively comprises: 53. The method of claim 52, comprising providing an aerosol, said predetermined portion being of sufficient length to provide a measured dose to each subject traversing said predetermined portion of said queue path at walking speed. described method. sequentially reading identifying information from each subject passing through the aerosol;
53. The method of claim 52, further comprising: storing information representative of each subject passing through the aerosol. continuously identifying information from each subject passing through said aerosol via at least one machine-readable symbol reader, radio frequency identification (RFID) interrogator, or via a facial recognition-based camera and processor-based computer system; a step of reading into
55. The method of claim 54, further comprising: storing information representing the amount of time each subject was exposed to the aerosol on at least one non-transitory processor-readable medium. 51. The method of claim 50, wherein generating a droplet aerosol comprises generating a droplet aerosol wherein the salt-based composition is a purely sanitary composition. 51. The method of claim 50, wherein generating an aerosol of droplets comprises administering a therapeutically effective amount of said salt-based composition to said subject to generate an aerosol of droplets for inhibiting viral shedding. described method. wherein the method of administering the formulation or composition to the nose, trachea and main bronchi of the respiratory tract of the subject while the subject is tilting the head back or in a reclining position that promotes post-nasal drip; 32. The method of claim 31, comprising administering the salt-based composition to the nose of the subject. administering the salt-based composition to the nose of the subject administering the salt-based composition to the nose of the subject for 5-10 seconds while the subject's head is tilted 60. The method of claim 59, comprising the step of: administering the salt-based composition to the nose of the subject administering the salt-based composition to the nose of the subject for 30 seconds or more while the subject is in a reclining position; 60. The method of claim 59, comprising A method of inhibiting exhalation of particles in the upper respiratory tract of a subject, comprising:
generating an aerosol of droplets of a salt-based composition comprising calcium chloride and/or magnesium chloride, said droplets having a mass median droplet diameter ranging from about 7 microns to about 15 microns. , the step;
administering said aerosol of droplets to airway mucosal mucus in said subject's nose, trachea and main bronchi, thereby suppressing said exhalation of particles in said subject's upper respiratory tract. 63. The method of claim 62, wherein generating an aerosol of droplets comprises generating an aerosol of droplets comprising calcium chloride and/or magnesium chloride in water. 64. The method of any of claims 62 or 63, wherein administering the aerosol of droplets comprises administering the aerosol of droplets while suspended in a stationary cloud. A delivery system operable to deliver a purely hygienic or antimicrobial formulation or composition to the nasal, tracheal and major bronchi of a subject's respiratory tract, said delivery system comprising:
a reservoir having at least one wall that at least partially separates an interior of the reservoir from an exterior thereof, the reservoir having a port that provides a fluid communication path between the interior of the reservoir and its exterior; said reservoir, at least in use, holding said hygienic or antimicrobial formulation or composition comprising a quantity of water and at least calcium chloride and/or magnesium chloride dissolved in said water;
at least one delivery device, said at least one delivery device comprising readily soluble droplets having a mass median diameter range of about 7 microns to about 15 microns; A delivery system comprising: said delivery device operable to cause formation of an aerosol comprising calcium. said at least one delivery device comprising at least one orifice having a size ranging from 3.5 microns to 7.5 microns and at least one pump operable to dispense a jet from said at least one orifice; 66. The delivery system of claim 65, comprising: the at least one delivery device comprising:
at least one nebulizer delivery device, said at least one nebulizer delivery device comprising an actuator, said actuator comprising a readily soluble droplet having a mass median diameter range of about 7 microns to about 15 microns; 66. The delivery system of claim 65, comprising said nebulizer delivery device controllably operable on an active agent vehicle to cause formation of an aerosol comprising at least calcium chloride dissolved in said volume of water. . 68. The delivery system of claim 67, wherein said at least one nebulizer delivery device is a nebulizer and further comprising a respective control subsystem communicatively coupled to control said actuator. said at least one nebulizer delivery device comprising a mesh screen mounted for vibration, a microcontroller, and said mesh screen along at least one axis in response to signals from said microcontroller to dispense an aerosol. 68. The delivery system of claim 67, wherein the nebulizer includes at least one of a piezoelectric transducer, a solenoid, or an electric motor drivingly coupled to vibrate the. 68. The delivery of claim 67, further comprising at least one switch or sensor communicatively connected to the microcontroller, the microcontroller being operable to generate a signal to operate the actuator in response. system. communicatively connected to the microcontroller and operable to generate a signal to the microcontroller to operate the actuator in response to the at least one nebulizer delivery device being tilted with respect to a normal position or an upright position; 68. The delivery system of claim 67, further comprising at least one switch or sensor. at least one switch or sensor communicatively coupled to the microcontroller and responsive to the position or orientation of a container and operable to generate a signal that causes the microcontroller to operate the actuator in accordance with the orientation of the container; 68. The delivery system of claim 67, further comprising: 68. The delivery device of claim 67, wherein said at least one nebulizer delivery device is removably dockable to said reservoir. a measured amount of calcium chloride and/or magnesium chloride;
a container sized to receive a defined amount of water for dissolving the calcium chloride;
A kit for suppressing exhalation of particles in the upper respiratory tract of a subject, comprising instructions. 75. The kit of claim 74, wherein said quantity of calcium chloride and/or magnesium chloride is self-sealed. 75. The kit of claim 74, further comprising, apart from said measured amount of calcium chloride, at least one measured amount of distilled or sterile water sealed in its own sealed package. A method of administering a formulation or composition to the nose, trachea and main bronchi of a subject's respiratory tract comprising:
generating an aerosol of droplets in a space from which the aerosol can be inhaled by the subject into the nose, trachea and main bronchi of the airways of the subject without the application of force. and
said droplet aerosol comprises a salt-based composition comprising calcium chloride and/or magnesium chloride in water;
The method of administering the formulation or composition to the nose, trachea and main bronchi of the respiratory tract of the subject while the subject tilts the head back or is in a reclining position that promotes post nasal drip. 2., accomplished by spraying said salt-based composition into said nose of said subject. A composition of aerosol droplets comprising a salt-based composition,
about 1% to about 5% by weight of calcium chloride and benzalkonium chloride preservatives in water, or
A composition of aerosol droplets comprising a salt-based composition comprising a sufficient amount of acid to lower the pH of said salt-based composition to about 2 to about 3. 79. The composition of claim 78, wherein said salt-based composition further comprises magnesium chloride. 80. The composition of any of claims 78 or 79, wherein said droplets have a mass median droplet diameter in the range of 7 microns to 15 microns. 81. The composition of claim 80, wherein a majority of said droplets have a droplet size between 9 microns and 10 microns in diameter. 79. The composition of claim 78, wherein said salt-based composition comprises a benzalkonium chloride preservative, said benzalkonium chloride being present in an amount ranging from about 0.05% to about 0.2% by weight. thing. 79. The composition of claim 78, wherein said salt-based composition comprises said acid, said acid being citric acid, hydrochloric acid, or a combination thereof. 79. The composition of claim 78, wherein said composition is in the form of a 20-30 mg dose. 85. The method of claim 84, wherein a dose of formulation of 20 mg to 30 mg is administered intranasally to the subject.

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